GenVue Discovery
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Showing variants that contain the term
Below are conditions that were reviewed by an expert panel and/or are in the Genetic Testing Registry (GTR) according to ClinVar. The data presented does not diagnose disease and has no guarantees of reporting accuracy. We report heterozygous variants as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
HFE
Variant:
c.187C>G
(p.His63Asp)
rsID: rs1799945
Ref Allele: C
Alt Allele: G
Freq: 10.1156%
CADD: 12.32
ClinVar Submissions (12)
HFE hemochromatosis is characterized by inappropriately high absorption of iron by the small intestinal mucosa. The phenotypic spectrum of HFE hemochromatosis includes: Persons with clinical HFE hemochromatosis, in whom manifestations of end-organ damage secondary to iron overload are present; Individuals with biochemical HFE hemochromatosis, in whom transferrin-iron saturation is increased and the only evidence of iron overload is increased serum ferritin concentration; and Non-expressing p.Cys282Tyr homozygotes, in whom neither clinical manifestations of HFE hemochromatosis nor iron overload are present. Clinical HFE hemochromatosis is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and anterior pituitary gland. In untreated individuals, early symptoms include: abdominal pain, weakness, lethargy, weight loss, arthralgias, diabetes mellitus; and increased risk of cirrhosis when the serum ferritin is higher than 1,000 ng/mL. Other findings may include progressive increase in skin pigmentation, congestive heart failure, and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE hemochromatosis is more common in men than women.
Last Evaluated: Jul 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 12
Clinical Significance: Pathogenic, other, risk factor
Assembly: GRCh38
Chromosome/Position: 6:26090951
OMIM Allelic Variant: 613609.0002
HFE hemochromatosis is characterized by inappropriately high absorption of iron by the small intestinal mucosa. The phenotypic spectrum of HFE hemochromatosis includes: Persons with clinical HFE hemochromatosis, in whom manifestations of end-organ damage secondary to iron overload are present; Individuals with biochemical HFE hemochromatosis, in whom transferrin-iron saturation is increased and the only evidence of iron overload is increased serum ferritin concentration; and Non-expressing p.Cys282Tyr homozygotes, in whom neither clinical manifestations of HFE hemochromatosis nor iron overload are present. Clinical HFE hemochromatosis is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and anterior pituitary gland. In untreated individuals, early symptoms include: abdominal pain, weakness, lethargy, weight loss, arthralgias, diabetes mellitus; and increased risk of cirrhosis when the serum ferritin is higher than 1,000 ng/mL. Other findings may include progressive increase in skin pigmentation, congestive heart failure, and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE hemochromatosis is more common in men than women.
Last Evaluated: Jul 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 12
Clinical Significance: Pathogenic, other, risk factor
Assembly: GRCh38
Chromosome/Position: 6:26090951
OMIM Allelic Variant: 613609.0002
Last Evaluated: Jul 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 12
Clinical Significance: Pathogenic, other, risk factor
Assembly: GRCh38
Chromosome/Position: 6:26090951
OMIM Allelic Variant: 613609.0002
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 12
Clinical Significance: Pathogenic, other, risk factor
Assembly: GRCh38
Chromosome/Position: 6:26090951
OMIM Allelic Variant: 613609.0002
Low clinical importance, Uncertain pathogenic — There have been some hypotheses that this variant contributes to causing hereditary hemochromatosis, possibly as a compound heterozygote, but some others treat it as a polymorphism. Cys282Tyr is the classic causal variant and itself has very low penetrance. Mouse studies indicates this variant has a similar but weaker effect; if it has any effect at all its penetrance may be quite low and/or require modifier alleles.
Expert Reviewed Clinically Significant Pathogenic, other, risk factor
Hetero
Gene:
MTHFR
Variant:
c.665C>T
(p.Ala222Val)
rsID: rs1801133
Ref Allele: G
Alt Allele: A
Freq: 28.9739%
CADD: 27.5
ClinVar Submissions (10)
Gastrointestinal stromal tumors are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (Miettinen et al., 1999, 1999). GISTs can also be seen in neurofibromatosis-1 (NF1; 162200) due to mutations in the NF1 gene, and are thus distinct from the GISTs described here. Sandberg and Bridge (2002) reviewed the cytogenetics and molecular genetics of gastrointestinal stromal tumors. Coffey et al. (2007) reviewed the clinical features, pathogenesis, and molecular treatments of Menetrier disease (137280) and GIST, both of which are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Methylenetetrahydrofolate Reductase (MTHFR) Deficiency is the most common genetic cause of elevated levels of homocysteine in the plasma (hyperhomocysteinemia). The MTHFR enzyme plays an important role in processing amino acids, specifically, the conversion of homocysteine to methionine. Genetic variations in the MTHFR gene can lead to impaired function or inactivation of this enzyme, which results in mildly elevated levels of homocysteine, especially in individuals who are also deficient in folate. In these individuals, a daily supplement of low dose folic acid may reduce and often normalize their homocysteine levels, but this has not been demonstrated to improve health outcomes. A common genetic variant in the MTHFR gene is a 677C>T polymorphism (NM_005957.4:c.665C>T, rs1801133). This variant encodes a thermolabile enzyme that is less active at higher temperatures. Individuals who carry two copies of this variant (“TT homozygous”) tend to have higher homocysteine levels and lower serum folate levels compared to controls. More than 25% of Hispanics and around 10-15% of North America Caucasians are estimated to be homozygous for the “thermolabile” variant (TT genotype). The TT genotype is least common in individuals of African descent (6%). Another common MTHFR variant, 1298A>C (NM_005957.4:c.1286A>C, rs1801131), does not cause increased homocysteine levels in heterozygous or homozygous individuals, but combined heterozygosity of 1298A>C and 677C>T results in an outcome similar to TT homozygous individuals. Until recently, it was thought that MTHFR deficiency, by causing elevated homocysteine levels, led to an increased risk of venous thrombosis, coronary heart disease, and recurrent pregnancy loss. However, more recent analysis has not found an association between elevated homocysteine levels and the risk of venous thrombosis or the risk of coronary heart disease. MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia, recurrent pregnancy loss, or for at-risk family members. Rarely, more severe variants in the MTHFR gene can be a cause of an autosomal recessive inborn error or metabolism where extremely high levels of homocysteine accumulate in the urine and plasma. This can cause developmental delay, eye disorders, thrombosis, and osteoporosis. But more commonly, homocystinuria is caused by variants in a different gene (cystathionine beta-synthase, CBS).
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
In a review article on the genetic predisposition to gastric cancer, Bevan and Houlston (1999) concluded that several genes may be associated with an increased risk of gastric cancer. Gastric cancer is a manifestation of a number of inherited cancer predisposition syndromes, including hereditary nonpolyposis colon cancer (HNPCC1; see 120435), familial adenomatous polyposis (FAP; 175100), Peutz-Jeghers syndrome (PJS; 175200), Cowden disease (CD; 158350), and the Li-Fraumeni syndrome (151623). See also hereditary diffuse gastric cancer (HDGC; 137215). Canedo et al. (2007) provided a review of genetic susceptibility to gastric cancer in patients infected with Helicobacter pylori (see 600263).
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Neural tube defects have a birth incidence of approximately 1 in 1,000 in American Caucasians and are the second most common type of birth defect after congenital heart defects. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly (206500) (Detrait et al., 2005). Women with elevated plasma homocysteine, low folate, or low vitamin B12 (cobalamin) are at increased risk of having a child with a neural tube defect (O'Leary et al., 2005). Motulsky (1996) cited evidence from the Centers for Disease Control ( Anonymous, 1992) that folic acid given before and during the first 4 weeks of pregnancy can prevent 50% or more of neural tube defects. Botto et al. (1999) and Detrait et al. (2005) provided reviews of neural tube defects. De Marco et al. (2006) provided a detailed review of neurulation and the possible etiologies of neural tube defects.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Formation of a blood clot (thrombus) inside a vein, causing the obstruction of blood flow.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Insufficiently evaluated pharmacogenetic — this is a.k.a. C677T and Rs1801133. Modulates toxicity of methotrexate in patients.
Expert Reviewed Clinically Significant Conflicting/Uncertain
Hetero
Gene:
CCDC170
Variant:
g.151627231G>A
rsID: rs2046210
Ref Allele: G
Alt Allele: A
Freq: 42.4017%
CADD: 0.277
ClinVar Submissions (1)
Estrogen resistance (ESTRR) is characterized by absence of puberty with elevated estradiol and gonadotropic hormones, as well as markedly delayed bone maturation. Female patients show absent breast development, small uterus, and enlarged multicystic ovaries; male patients may show small testes (Bernard et al., 2017). Some patients exhibit continued growth into adulthood (Smith et al., 1994).
Last Evaluated: Mar 01, 2014
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: 6:151627231
Expert Reviewed Clinically Significant Likely pathogenic
Hetero
Gene:
LCT;MCM6
Variant:
c.-13907C>T
rsID: rs4988235
Ref Allele: G
Alt Allele: A
Freq: 38.7662%
CADD: 10.75
ClinVar Submissions (1)
Last Evaluated: Nov 20, 2018
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: association
Assembly: GRCh38
Chromosome/Position: 2:135851076
OMIM Allelic Variant: 601806.0001
Expert Reviewed
Hetero
Gene:
CCDC170;ESR1
Variant:
c.1710+1144T>G
rsID: rs12662670
Ref Allele: T
Alt Allele: G
Freq: 8.2195%
CADD: 2.416
ClinVar Submissions (1)
Estrogen resistance (ESTRR) is characterized by absence of puberty with elevated estradiol and gonadotropic hormones, as well as markedly delayed bone maturation. Female patients show absent breast development, small uterus, and enlarged multicystic ovaries; male patients may show small testes (Bernard et al., 2017). Some patients exhibit continued growth into adulthood (Smith et al., 1994).
Last Evaluated: Mar 01, 2014
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:151597721
Expert Reviewed Conflicting/Uncertain
Hetero
Gene:
BTD
Variant:
c.1336G>C
(p.Asp446His)
rsID: rs13078881
Ref Allele: G
Alt Allele: C
Freq: 2.5667%uncommon
CADD: 23.3
ClinVar Submissions (15)
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
Low clinical importance, pathogenic — This variant is implicated in partial and profound biotinidase deficiency. Alone, this variant is estimated to have a 52% loss of enzymatic activity. This variant is often found with A171T, and together they are reported to cause profound deficiency. Notably there is a report of asymptomatic double-mutant adults, so symptoms may have variable penetrance. This variant is found compound heterozygously with more serious mutations in cases of partial biotinidase deficiency.
Expert Reviewed Clinically Significant Conflicting/Uncertain
Hetero
Below are drug responses that were reviewed by an expert panel according to ClinVar. The data presented has no guarantees of reporting accuracy. Heterozygous variants are reported as yellow and homozygous variants as red. Reference alleles may be modified to match risk. While a red or yellow variant could indicate a suboptimal response to drug, it doesn't necessarily mean one won't respond well to it. This is for research and educational purposes only.
Gene:
GSTP1
Variant:
c.313A>G
(p.Ile105Val)
rsID: rs1695
Ref Allele: A
Alt Allele: G
Freq: 37.0731%
CADD: 4.014
ClinVar Submissions (2)
A benign or malignant neoplasm that affects the colon or rectum. Representative examples of benign neoplasms include lipoma and leiomyoma. Representative examples of malignant neoplasms include carcinoma, lymphoma, and sarcoma. Colorectal adenomas always exhibit epithelial dysplasia and are considered premalignant neoplasms.
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:67585218
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:67585218
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:67585218
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:67585218
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:67585218
Insufficiently evaluated pharmacogenetic — Hematological toxicity with fluoruracil.
Expert Reviewed drug response
Hetero
Gene:
CYP19A1
Variant:
c.*161T>G
rsID: rs4646
Ref Allele: A
Alt Allele: C
Freq: 70.0545%
CADD: 0.652
ClinVar Submissions (2)
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Insufficiently evaluated pharmacogenetic — associated with response to a drug letrozole in cancer patients
Expert Reviewed drug response
Hetero
Gene:
COMT
Variant:
c.472G>A
(p.Val158Met)
rsID: rs4680
Ref Allele: G
Alt Allele: A
Freq: 42.4264%
CADD: 12.4
ClinVar Submissions (3)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:19963748
OMIM Allelic Variant: 116790.0001
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:19963748
OMIM Allelic Variant: 116790.0001
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:19963748
OMIM Allelic Variant: 116790.0001
Insufficiently evaluated pathogenic — A codominant allele affecting COMT enzyme activity, considered a benign functional polymorphism. Some claims of association with schizophrenia, Possibly provides advantage in memory and attention tasks ("worrier strategy").
Expert Reviewed drug response
Hetero
Gene:
SOD2
Variant:
c.47T>C
(p.Val16Ala)
rsID: rs4880
Ref Allele: A
Alt Allele: G
Freq: 45.7529%
CADD: 12.94
ClinVar Submissions (2)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:159692840
OMIM Allelic Variant: 147460.0001
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:159692840
OMIM Allelic Variant: 147460.0001
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:159692840
OMIM Allelic Variant: 147460.0001
Expert Reviewed drug response
Hetero
Gene:
ADD1
Variant:
c.1378G>T
(p.Gly460Trp)
rsID: rs4961
Ref Allele: G
Alt Allele: T
Freq: 18.0794%
CADD: 25.2
ClinVar Submissions (2)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:2904980
OMIM Allelic Variant: 102680.0001
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:2904980
OMIM Allelic Variant: 102680.0001
Insufficiently evaluated pathogenic — This variant is associated with salt-sensitivity in patients with hypertension.
Expert Reviewed drug response
Hetero
Gene:
GNB3
Variant:
c.825C>T
(p.Ser275=)
rsID: rs5443
Ref Allele: C
Alt Allele: T
Freq: 46.124%
CADD: 0.665
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:6845711
Expert Reviewed drug response
Hetero
Gene:
GP1BA
Variant:
c.482C>T
(p.Thr161Met)
rsID: rs6065
Ref Allele: C
Alt Allele: T
Freq: 12.7891%
CADD: 0.188
ClinVar Submissions (2)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:4933086
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:4933086
Expert Reviewed drug response
Hetero
Gene:
HTR1A
Variant:
c.-1019G>C
rsID: rs6295
Ref Allele: C
Alt Allele: G
Freq: 49.9873%
CADD: 2.67
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:63962738
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:63962738
Expert Reviewed drug response
Hetero
Gene:
ERCC1
Variant:
c.354T>C
(p.Asn118=)
rsID: rs11615
Ref Allele: A
Alt Allele: G
Freq: 57.5449%
CADD: 1.504
ClinVar Submissions (2)
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Expert Reviewed drug response
Hetero
Gene:
XRCC1
Variant:
c.1196A>G
(p.Gln399Arg)
rsID: rs25487
Ref Allele: T
Alt Allele: C
Freq: 71.5477%
CADD: 17.31
ClinVar Submissions (1)
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:43551574
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:43551574
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:43551574
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:43551574
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:43551574
Expert Reviewed drug response
Hetero
Gene:
FCGR3A
Variant:
c.526T>G
(p.Phe176Val)
rsID: rs396991
Ref Allele: A
Alt Allele: C
Freq: 33.5786%
CADD: 0.104
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161544752
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161544752
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161544752
Insufficiently evaluated pharmacogenetic — Better response with cetuximab and rituximab.
Expert Reviewed drug response
Homo
Gene:
CHRNA3
Variant:
c.1390-2867C>T
rsID: rs578776
Ref Allele: G
Alt Allele: A
Freq: 41.4795%
CADD: 0.96
ClinVar Submissions (1)
Last Evaluated: Apr 12, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78596058
Expert Reviewed drug response
Hetero
Gene:
APOA5
Variant:
c.-644C>T
rsID: rs662799
Ref Allele: G
Alt Allele: A
Freq: 89.5929%
CADD: 3.29
ClinVar Submissions (1)
Last Evaluated: May 14, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:116792991
Last Evaluated: May 14, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:116792991
Last Evaluated: May 14, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:116792991
Insufficiently evaluated pharmacogenetic — associated with the triglyceride levels and the risk of first heart attack
Expert Reviewed drug response
Homo
Gene:
DYNC2H1
Variant:
g.103547430A>G
rsID: rs716274
Ref Allele: A
Alt Allele: G
Freq: 49.5676%
CADD: 2.369
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:103547430
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:103547430
Expert Reviewed drug response
Homo
Gene:
LTC4S
Variant:
c.-444A>C
rsID: rs730012
Ref Allele: A
Alt Allele: C
Freq: 20.467%
CADD: 0.694
ClinVar Submissions (1)
Last Evaluated: Oct 28, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:179793637
Expert Reviewed drug response
Hetero
Gene:
CCHCR1
Variant:
c.1581-597T>C
rsID: rs746647
Ref Allele: A
Alt Allele: G
Freq: 28.1162%
CADD: 5.566
ClinVar Submissions (1)
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:31146405
Expert Reviewed drug response
Hetero
Gene:
UGT1A1
Variant:
c.-364C>T
rsID: rs887829
Ref Allele: C
Alt Allele: T
Freq: 34.8847%
CADD: 8.026
ClinVar Submissions (1)
Last Evaluated: Mar 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:233759924
Expert Reviewed drug response
Hetero
Gene:
LOC100996325
Variant:
n.366+1469G>A
rsID: rs924607
Ref Allele: C
Alt Allele: T
Freq: 30.6416%
CADD: 1.592
ClinVar Submissions (1)
Last Evaluated: Feb 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:609978
Expert Reviewed drug response
Hetero
Gene:
NAT2
Variant:
c.282C>T
(p.Tyr94=)
rsID: rs1041983
Ref Allele: C
Alt Allele: T
Freq: 36.3604%
CADD: 0.032
ClinVar Submissions (1)
Last Evaluated: Oct 27, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:18400285
Expert Reviewed drug response
Hetero
Gene:
TP53
Variant:
c.215C>G
(p.Pro72Arg)
rsID: rs1042522
Ref Allele: G
Alt Allele: C
Freq: 61.6654%
CADD: 6.813
ClinVar Submissions (15)
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Low clinical importance, Uncertain pathogenic — This is a common variant was first reported as a polymorphism. It has since had mixed associations with cancer: Storey et al. conclude a 7x *increased* risk of HPV cancer for homozygotes vs hets, but Jones et al. find a 1.98x *decreased* risk for colorectal cancer. This variant may have significant impact on particular cancers, but it is unclear what effect it has on the overall burden of cancer.
Expert Reviewed drug response
Hetero
Gene:
ADRB2
Variant:
c.46A=
(p.Arg16=)
rsID: rs1042713
Ref Allele: G
Alt Allele: A
Freq: 42.6104%
CADD: 16.81
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:148826877
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:148826877
Expert Reviewed drug response
Hetero
Gene:
ABCB1
Variant:
c.3435T>C
(p.Ile1145=)
rsID: rs1045642
Ref Allele: A
Alt Allele: G
Freq: 59.2492%
CADD: 0.015
ClinVar Submissions (3)
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Expert Reviewed drug response
Hetero
Gene:
CHRNA3
Variant:
c.645C>T
(p.Tyr215=)
rsID: rs1051730
Ref Allele: G
Alt Allele: A
Freq: 24.3932%
CADD: 22.5
ClinVar Submissions (2)
Last Evaluated: Apr 01, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78601997
OMIM Allelic Variant: 118503.0001
Last Evaluated: Apr 01, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78601997
OMIM Allelic Variant: 118503.0001
Last Evaluated: Apr 01, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78601997
OMIM Allelic Variant: 118503.0001
Expert Reviewed drug response
Hetero
Gene:
EPHX1
Variant:
c.337T>C
(p.Tyr113His)
rsID: rs1051740
Ref Allele: T
Alt Allele: C
Freq: 27.8279%
CADD: 26.4
ClinVar Submissions (2)
Last Evaluated: Sep 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:225831932
OMIM Allelic Variant: 132810.0001
Last Evaluated: Sep 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:225831932
OMIM Allelic Variant: 132810.0001
Insufficiently evaluated pharmacogenetic — This gene is involved in response to oxidative stress, and the 113H variant is associated with lower enzyme activity, apparently through disruption of protein stability rather than enzymatic function of the protein itself. Several studies have attempted to link this variant to cancer, lung disease, and other associations, but it is unclear which of these are results reproducible and validated.
Expert Reviewed drug response
Hetero
Gene:
ITPA
Variant:
c.94C>A
(p.Pro32Thr)
rsID: rs1127354
Ref Allele: C
Alt Allele: A
Freq: 6.5765%
CADD: 22.1
ClinVar Submissions (2)
Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency is a common inherited condition characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes (Sumi et al., 2002).
Last Evaluated: Aug 05, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 20:3213196
OMIM Allelic Variant: 147520.0001
Last Evaluated: Aug 05, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 20:3213196
OMIM Allelic Variant: 147520.0001
Last Evaluated: Aug 05, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 20:3213196
OMIM Allelic Variant: 147520.0001
Low clinical importance, pharmacogenetic — This variant is associated with inosine triphosphate pyrophosphohydrolase deficiency and may be associated with an adverse reaction to thiopurine drugs (which are used as immunosuppressants). Homozygotes have no detectable ITPase activity, individuals compound heterozygous with another less severe mutation also have severely reduced enzyme activity.
Expert Reviewed drug response
Hetero
Gene:
GATM
Variant:
c.-394-272A>G
rsID: rs1346268
Ref Allele: T
Alt Allele: C
Freq: 33.4942%
CADD: 5.676
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45380831
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45380831
Expert Reviewed drug response
Hetero
Gene:
HTR2C
Variant:
c.551-3008C>G
rsID: rs1414334
Ref Allele: C
Alt Allele: G
Freq: 76.7066%
ClinVar Submissions (2)
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia. Clozapine is also used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. Compared to typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill patients who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood counts and absolute neutrophil counts, and in the US, the FDA requires that patients receiving clozapine be enrolled in a computer-based registry. Clozapine is metabolized in the liver by the cytochrome P450 (CYP) system of enzymes. CYP1A2 is the main CYP isoform in clozapine metabolism and CYP1A2 activity is an important determinant of clozapine dose. Other CYP enzymes involved in clozapine metabolism include CYP2D6 and CYP3A4. Approximately 6-10% of Caucasians have reduced activity of CYP2D6 ("poor metabolizers"). These individuals may develop higher than expected plasma concentrations of clozapine with usual doses. The FDA-approved drug label for clozapine states that a dose reduction may be necessary in patients who are CYP2D6 poor metabolizers.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Expert Reviewed drug response
Homo
Gene:
C8orf34
Variant:
c.736+8162C>G
rsID: rs1517114
Ref Allele: C
Alt Allele: G
Freq: 62.6147%
CADD: 0.335
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:68476982
Expert Reviewed drug response
Homo
Gene:
CETP
Variant:
c.658+186C>A
rsID: rs1532624
Ref Allele: C
Alt Allele: A
Freq: 33.2585%
CADD: 8.322
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:56971567
Expert Reviewed drug response
Hetero
Gene:
-
Variant:
g.45328787C>T
rsID: rs1719247
Ref Allele: C
Alt Allele: T
Freq: 45.776%
CADD: 3.114
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45328787
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45328787
Expert Reviewed drug response
Hetero
Gene:
ABCC4
Variant:
c.3348G>A
(p.Lys1116=)
rsID: rs1751034
Ref Allele: C
Alt Allele: T
Freq: 78.5089%
CADD: 7.895
ClinVar Submissions (1)
Last Evaluated: May 15, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:95062722
Expert Reviewed drug response
Homo
Gene:
NAT2
Variant:
c.590G>A
(p.Arg197Gln)
rsID: rs1799930
Ref Allele: G
Alt Allele: A
Freq: 27.0889%
CADD: 18.73
ClinVar Submissions (2)
Last Evaluated: Oct 27, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:18400593
OMIM Allelic Variant: 612182.0001
Last Evaluated: Oct 27, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:18400593
OMIM Allelic Variant: 612182.0001
Insufficiently evaluated pharmacogenetic — This allele characterizes the NAT2*6A haplotype which causes slow acetylation.
Expert Reviewed drug response
Hetero
Gene:
FCGR2A
Variant:
c.497A>G
(p.His166Arg)
rsID: rs1801274
Ref Allele: A
Alt Allele: G
Freq: 50.5431%
CADD: 0.08
ClinVar Submissions (3)
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Expert Reviewed drug response
Hetero
Gene:
MTRR
Variant:
c.66A>G
(p.Ile22Met)
rsID: rs1801394
Ref Allele: A
Alt Allele: G
Freq: 43.3765%
CADD: 20.7
ClinVar Submissions (6)
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Low clinical importance, Likely pathogenic — This common variant (HapMap allele frequency of 31.3%) in a protein involved in folate (B9) and cobalamin (B12) metabolism and is often reported as "MTRR I22M" (an alternative transcript position). Mothers homozygous for this variant are associated with having around a increased chance of a child with Down syndrome (risk of 0.4%, average risk in population is 0.25%). Notably, age plays a far larger role in the rate of Down syndrome (risk is 4.5% for a mother 45-years-of-age), and it is unknown how this variant may combine with the effect of age. There are conflicting reports associating this variant with incidence of neural tube defects, possibly when combined with MTHFR A222V.
Expert Reviewed drug response
Hetero
Gene:
CRHR1
Variant:
c.1194+111C>T
rsID: rs1876828
Ref Allele: C
Alt Allele: T
Freq: 14.7992%
CADD: 6.162
ClinVar Submissions (1)
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:45834159
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:45834159
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:45834159
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:45834159
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:45834159
Expert Reviewed drug response
Hetero
Gene:
UGT2B15
Variant:
c.253T>G
(p.Tyr85Asp)
rsID: rs1902023
Ref Allele: A
Alt Allele: C
Freq: 52.3358%
CADD: 0.027
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:68670366
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:68670366
Expert Reviewed drug response
Hetero
Gene:
GRIK4
Variant:
c.83-10039T>C
rsID: rs1954787
Ref Allele: T
Alt Allele: C
Freq: 46.3279%
CADD: 0.336
ClinVar Submissions (2)
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:120792654
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:120792654
Expert Reviewed drug response
Hetero
Gene:
ABCB1
Variant:
c.2677T>G
(p.Ser893Ala)
rsID: rs2032582
Ref Allele: A
Alt Allele: C
Freq: 67.0951%
CADD: 13.16
ClinVar Submissions (3)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87531302
OMIM Allelic Variant: 171050.0003
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87531302
OMIM Allelic Variant: 171050.0003
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87531302
OMIM Allelic Variant: 171050.0003
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87531302
OMIM Allelic Variant: 171050.0003
Expert Reviewed drug response
Hetero
Gene:
CYP4F2
Variant:
c.1297G>A
(p.Val433Met)
rsID: rs2108622
Ref Allele: C
Alt Allele: T
Freq: 22.5551%
CADD: 24.8
ClinVar Submissions (1)
Last Evaluated: Apr 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:15879621
Last Evaluated: Apr 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:15879621
Last Evaluated: Apr 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:15879621
Last Evaluated: Apr 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:15879621
Insufficiently evaluated pharmacogenetic — Requires 1mg/day greater dose of warfarin.
Expert Reviewed drug response
Hetero
Gene:
TMEM43;XPC
Variant:
c.2815C>A
(p.Gln939Lys)
rsID: rs2228001
Ref Allele: G
Alt Allele: T
Freq: 64.307%
CADD: 14.73
ClinVar Submissions (4)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 3:14145949
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 3:14145949
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 3:14145949
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 3:14145949
Expert Reviewed drug response
Hetero
Gene:
VDR
Variant:
c.2T>C
(p.Met1Thr)
rsID: rs2228570
Ref Allele: A
Alt Allele: G
Freq: 65.9746%
CADD: 24.6
ClinVar Submissions (3)
Last Evaluated: Mar 01, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:47879112
Last Evaluated: Mar 01, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:47879112
Last Evaluated: Mar 01, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:47879112
Expert Reviewed drug response
Homo
Gene:
CYP2B6
Variant:
c.823-197T>C
rsID: rs2279345
Ref Allele: T
Alt Allele: C
Freq: 67.6653%
CADD: 1.711
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41009797
Expert Reviewed drug response
Homo
Gene:
FDPS
Variant:
c.-1-98T>G
rsID: rs2297480
Ref Allele: T
Alt Allele: G
Freq: 30.5492%
CADD: 4.553
ClinVar Submissions (1)
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:155309691
Expert Reviewed drug response
Hetero
Gene:
CYP3A4
Variant:
c.-392G>A
rsID: rs2740574
Ref Allele: C
Alt Allele: T
Freq: 77.7308%
CADD: 3.399
ClinVar Submissions (2)
Last Evaluated: Feb 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:99784473
OMIM Allelic Variant: 124010.0001
Last Evaluated: Feb 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:99784473
OMIM Allelic Variant: 124010.0001
Last Evaluated: Feb 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:99784473
OMIM Allelic Variant: 124010.0001
Expert Reviewed drug response
Homo
Gene:
VKORC1
Variant:
c.173+324T>G
rsID: rs2884737
Ref Allele: A
Alt Allele: C
Freq: 16.7232%
CADD: 3.96
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31094233
Expert Reviewed drug response
Hetero
Gene:
-
Variant:
g.207629510T>C
rsID: rs2952768
Ref Allele: T
Alt Allele: C
Freq: 34.9683%
CADD: 6.283
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Expert Reviewed drug response
Hetero
Gene:
ERCC1
Variant:
c.*197G>T
rsID: rs3212986
Ref Allele: C
Alt Allele: A
Freq: 27.718%
CADD: 0.61
ClinVar Submissions (1)
Last Evaluated: Jun 27, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45409478
Last Evaluated: Jun 27, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45409478
Last Evaluated: Jun 27, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45409478
Expert Reviewed drug response
Hetero
Gene:
PTGFR
Variant:
c.-562T>C
rsID: rs3753380
Ref Allele: T
Alt Allele: C
Freq: 78.9891%
CADD: 6.726
ClinVar Submissions (1)
Last Evaluated: Jan 21, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:78490747
Expert Reviewed drug response
Hetero
Gene:
SCN1A
Variant:
c.603-91G>A
rsID: rs3812718
Ref Allele: C
Alt Allele: T
Freq: 47.6706%
CADD: 18.66
ClinVar Submissions (2)
Last Evaluated: Nov 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:166053034
OMIM Allelic Variant: 182389.0016
Last Evaluated: Nov 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:166053034
OMIM Allelic Variant: 182389.0016
Last Evaluated: Nov 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:166053034
OMIM Allelic Variant: 182389.0016
Last Evaluated: Nov 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:166053034
OMIM Allelic Variant: 182389.0016
Last Evaluated: Nov 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:166053034
OMIM Allelic Variant: 182389.0016
Expert Reviewed drug response
Hetero
Gene:
NEDD4L
Variant:
c.24G>A
(p.Gln8=)
rsID: rs4149601
Ref Allele: G
Alt Allele: A
Freq: 32.3896%
CADD: 6.379
ClinVar Submissions (1)
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:58149559
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:58149559
Expert Reviewed drug response
Homo
Gene:
ATIC
Variant:
c.1503+675T>C
rsID: rs4673993
Ref Allele: T
Alt Allele: C
Freq: 26.3801%
CADD: 1.942
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:215347616
Expert Reviewed drug response
Homo
Gene:
COQ2
Variant:
c.779-1022C>G
rsID: rs4693075
Ref Allele: G
Alt Allele: C
Freq: 61.6184%
CADD: 1.96
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:83271015
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:83271015
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:83271015
Expert Reviewed drug response
Hetero
Gene:
FKBP5
Variant:
c.-20+18122T>C
rsID: rs4713916
Ref Allele: A
Alt Allele: G
Freq: 77.1709%
CADD: 0.798
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Expert Reviewed drug response
Hetero
Gene:
CYP2B6
Variant:
c.485-18C>T
rsID: rs4803419
Ref Allele: C
Alt Allele: T
Freq: 26.6628%
CADD: 2.548
ClinVar Submissions (1)
Last Evaluated: Dec 11, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41006887
Expert Reviewed drug response
Hetero
Gene:
DPP6
Variant:
c.52-71279T>C
rsID: rs6977820
Ref Allele: T
Alt Allele: C
Freq: 58.4257%
CADD: 6.496
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:154374935
Expert Reviewed drug response
Homo
Gene:
SEMA3C
Variant:
c.103+13883A>G
rsID: rs7779029
Ref Allele: T
Alt Allele: C
Freq: 14.9521%
CADD: 0.448
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:80902796
Expert Reviewed drug response
Hetero
Gene:
CRHR2
Variant:
c.-166-546T>A
rsID: rs7793837
Ref Allele: A
Alt Allele: T
Freq: 40.9069%
CADD: 2.37
ClinVar Submissions (1)
Last Evaluated: Jul 05, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:30687161
Last Evaluated: Jul 05, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:30687161
Expert Reviewed drug response
Hetero
Gene:
TCF7L2
Variant:
c.382-41435C>T
rsID: rs7903146
Ref Allele: C
Alt Allele: T
Freq: 27.0921%
CADD: 3.637
ClinVar Submissions (2)
Type 2 diabetes is a disorder characterized by abnormally high blood sugar levels. In this form of diabetes, the body stops using and making insulin properly. Insulin is a hormone produced in the pancreas that helps regulate blood sugar levels. Specifically, insulin controls how much glucose (a type of sugar) is passed from the blood into cells, where it is used as an energy source. When blood sugar levels are high (such as after a meal), the pancreas releases insulin to move the excess glucose into cells, which reduces the amount of glucose in the blood.Most people who develop type 2 diabetes first have insulin resistance, a condition in which the body's cells use insulin less efficiently than normal. As insulin resistance develops, more and more insulin is needed to keep blood sugar levels in the normal range. To keep up with the increasing need, insulin-producing cells in the pancreas (called beta cells) make larger amounts of insulin. Over time, the beta cells become less able to respond to blood sugar changes, leading to an insulin shortage that prevents the body from reducing blood sugar levels effectively. Most people have some insulin resistance as they age, but inadequate exercise and excessive weight gain make it worse, greatly increasing the likelihood of developing type 2 diabetes.Type 2 diabetes can occur at any age, but it most commonly begins in middle age or later. Signs and symptoms develop slowly over years. They include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, tingling or loss of feeling in the hands and feet (diabetic neuropathy), sores that do not heal well, and weight loss. If blood sugar levels are not controlled through medication or diet, type 2 diabetes can cause long-lasting (chronic) health problems including heart disease and stroke; nerve damage; and damage to the kidneys, eyes, and other parts of the body.
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:112998590
OMIM Allelic Variant: 602228.0001
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:112998590
OMIM Allelic Variant: 602228.0001
Insufficiently evaluated pathogenic — associated with colorectal cancer for the T allele.
Expert Reviewed drug response
Hetero
Gene:
HTR2A
Variant:
c.614-2211T>C
rsID: rs7997012
Ref Allele: A
Alt Allele: G
Freq: 71.3279%
CADD: 11.64
ClinVar Submissions (3)
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Expert Reviewed drug response
Homo
Gene:
VKORC1
Variant:
c.283+124G>C
rsID: rs8050894
Ref Allele: C
Alt Allele: G
Freq: 39.1159%
CADD: 1.82
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093188
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093188
Expert Reviewed drug response
Homo
Gene:
IFNL3
Variant:
g.39252525T>G
rsID: rs8099917
Ref Allele: T
Alt Allele: G
Freq: 15.2539%
CADD: 15.16
ClinVar Submissions (1)
Last Evaluated: Oct 16, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39252525
Last Evaluated: Oct 16, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39252525
Expert Reviewed drug response
Hetero
Gene:
VKORC1
Variant:
c.174-136C>T
rsID: rs9934438
Ref Allele: G
Alt Allele: A
Freq: 33.6352%
CADD: 14.98
ClinVar Submissions (5)
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Warfarin is an oral anti-coagulant used world-wide to treat and prevent thrombotic disorders. While it is highly effective, it has a very narrow therapeutic index making it difficult to dose correctly. Genetic variants in both cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, along with non-genetic factors, are known to affect warfarin dose variability. Patients with specific variants in the gene CYP2C9 (the primary warfarin-metabolizing enzyme), such as CYP2C9*2 and CYP2C9*3, may require a lower dose of warfarin as compared to patients without these variants. Patients with a specific variant in VKORC1 (the target enzyme of warfarin), known as -1639G>A or rs9923231, may require a lower warfarin dose as compared to patients who do not have this variant. The combination of CYP2C9 and VKORC1 genetic variants, along with clinical factors, can put some patients at risk for adverse events such as bleeding. Guidelines regarding the use of pharmacogenomic tests in dosing for warfarin have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website.
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Insufficiently evaluated pharmacogenetic — gene VKORC1 SNP 1173 C>T is strongly associated with low warfarin dose requirement.
Expert Reviewed drug response
Homo
Gene:
SLCO1B1
Variant:
c.1865+4846T>C
rsID: rs11045879
Ref Allele: T
Alt Allele: C
Freq: 18.1639%
CADD: 6.151
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:21229685
Expert Reviewed drug response
Hetero
Gene:
C11orf65
Variant:
c.175-5285G>T
rsID: rs11212617
Ref Allele: C
Alt Allele: A
Freq: 47.0924%
CADD: 2.33
ClinVar Submissions (1)
Last Evaluated: Nov 17, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:108412434
Expert Reviewed drug response
Homo
Gene:
IFNL3
Variant:
c.259-126T>C
rsID: rs11881222
Ref Allele: A
Alt Allele: G
Freq: 29.6994%
CADD: 4.956
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39244283
Last Evaluated: Jun 14, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39244283
Last Evaluated: Jun 14, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39244283
Expert Reviewed drug response
Hetero
Gene:
IFNL3;IFNL4
Variant:
c.151-152G>A
rsID: rs12979860
Ref Allele: C
Alt Allele: T
Freq: 39.0673%
CADD: 1.703
ClinVar Submissions (2)
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
Expert Reviewed drug response
Hetero
Gene:
COMT;TXNRD2
Variant:
c.103+197G>A
rsID: rs13306278
Ref Allele: C
Alt Allele: T
Freq: 9.3591%
CADD: 8.327
ClinVar Submissions (1)
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:19941504
Expert Reviewed drug response
Hetero
Below are mutations from ClinVar that were submitted as "clinically significant." Variants shown may or may not be truly clinically significant. The data presented has no guarantees of reporting accuracy. Heterozygous variants are reported as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
REPS1
Variant:
c.338C>A
(p.Ala113Glu)
rsID: rs201191394
Ref Allele: G
Alt Allele: T
Freq: 0.0175%rare
CADD: 24.4
ClinVar Submissions (2)
Last Evaluated: Mar 27, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 6:138945637
OMIM Allelic Variant: 614825.0002
Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Ten types and their associated genes are recognized. The age of onset ranges from infancy to late adulthood; the rate of progression varies. Cognitive decline occurs in some subtypes, but more often cognition is relatively spared. Cerebellar atrophy is a frequent finding in some subtypes.
Last Evaluated: Mar 27, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 6:138945637
OMIM Allelic Variant: 614825.0002
Clinically Significant Pathogenic
Hetero
Gene:
FLCN
Variant:
c.1333G>A
(p.Ala445Thr)
rsID: rs41419545
Ref Allele: C
Alt Allele: T
Freq: 0.2126%rare
CADD: 1.994
ClinVar Submissions (11)
Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, stomach, ovary, small bowel, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following lifetime risks for cancer are seen: CRC: 52%-82% (mean age at diagnosis 44-61 years). Endometrial cancer in females: 25%-60% (mean age at diagnosis 48-62 years). Gastric cancer: 6%-13% (mean age at diagnosis 56 years). Ovarian cancer: 4%-12% (mean age at diagnosis 42.5 years; ~30% are diagnosed < age 40 years). The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, trichodiscomas/angiofibromas, perifollicular fibromas, and acrochordons), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear during the third and fourth decades of life and typically increase in size and number with age. Lung cysts are mostly bilateral and multifocal; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Individuals with BHDS are at a sevenfold increased risk for renal tumors that are typically bilateral and multifocal and usually slow growing; median age of tumor diagnosis is 48 years. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (so-called oncocytic hybrid tumor) and chromophobe histologic cell types. Some families have renal tumor and/or autosomal dominant spontaneous pneumothorax without cutaneous manifestations.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
Pneumothorax occurring without traumatic injury to the chest or lung.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
ATP8B1
Variant:
c.208G>A
(p.Asp70Asn)
rsID: rs34719006
Ref Allele: C
Alt Allele: T
Freq: 0.2572%rare
CADD: 23.7
ClinVar Submissions (4)
Intrahepatic cholestasis of pregnancy is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Some women with ICP may also be susceptible to oral contraceptive-induced cholestasis (OCIC) (summary by Pasmant et al., 2012). Genetic Heterogeneity of Intrahepatic Cholestasis of Pregnancy See also ICP3 (614972), caused by mutation in the ABCB4 gene (171060).
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57706561
OMIM Allelic Variant: 602397.0010
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57706561
OMIM Allelic Variant: 602397.0010
ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe to intermediate to mild, based on an individual's clinical findings and laboratory test results, including liver biopsy. Severe ATP8B1 deficiency is characterized by onset of symptoms of cholestasis (pruritus and attacks of jaundice) within the first few months of life. Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months. Without surgical intervention, cirrhosis and evolution to end-stage hepatic failure and death usually ensue before the third decade. Mild ATP8B1 deficiency is characterized by intermittent episodes of cholestasis manifest as severe pruritus and jaundice; chronic liver damage does not typically develop. In contrast to patients in whom bouts of cholestasis are induced only by particular triggers known to increase risk of cholestasis (drug exposure, shifts in hormonal milieu [including those resulting from ingestion of contraceptive drugs or from pregnancy], coexistent malignancy), some or all bouts of cholestasis in individuals with mild ATP8B1 deficiency have different or unknown triggers.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57706561
OMIM Allelic Variant: 602397.0010
ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe to intermediate to mild, based on an individual's clinical findings and laboratory test results, including liver biopsy. Severe ATP8B1 deficiency is characterized by onset of symptoms of cholestasis (pruritus and attacks of jaundice) within the first few months of life. Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months. Without surgical intervention, cirrhosis and evolution to end-stage hepatic failure and death usually ensue before the third decade. Mild ATP8B1 deficiency is characterized by intermittent episodes of cholestasis manifest as severe pruritus and jaundice; chronic liver damage does not typically develop. In contrast to patients in whom bouts of cholestasis are induced only by particular triggers known to increase risk of cholestasis (drug exposure, shifts in hormonal milieu [including those resulting from ingestion of contraceptive drugs or from pregnancy], coexistent malignancy), some or all bouts of cholestasis in individuals with mild ATP8B1 deficiency have different or unknown triggers.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57706561
OMIM Allelic Variant: 602397.0010
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57706561
OMIM Allelic Variant: 602397.0010
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
CTH
Variant:
c.200C>T
(p.Thr67Ile)
rsID: rs28941785
Ref Allele: C
Alt Allele: T
Freq: 0.7008%rare
CADD: 25.2
ClinVar Submissions (3)
Cystathioninuria, an autosomal recessive phenotype with no striking pathologic features, is characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Because of the inconsistency and wide variety of disease associations, cystathioninuria is considered to be a benign biochemical anomaly (Mudd et al., 2001).
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:70415987
OMIM Allelic Variant: 607657.0003
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:70415987
OMIM Allelic Variant: 607657.0003
Low clinical importance, pathogenic — Causes cystathioninuria in a recessive manner (an abnormal accumulation of cystathione in urine). Generally thought to be a benign anomaly, it's often only found when a clinician performs biochemical assays for investigating an unrelated disease.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
RBM8A
Variant:
c.-21G>A
rsID: rs139428292
Ref Allele: C
Alt Allele: T
Freq: 1.9456%uncommon
CADD: 8.717
ClinVar Submissions (7)
Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia (<50 platelets/nL) that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.
Last Evaluated: May 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Pathogenic/Likely pathogenic, other
Assembly: GRCh38
Chromosome/Position: 1:145927447
OMIM Allelic Variant: 605313.0001
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Pathogenic/Likely pathogenic, other
Assembly: GRCh38
Chromosome/Position: 1:145927447
OMIM Allelic Variant: 605313.0001
Clinically Significant Pathogenic/Likely pathogenic, other
Hetero
Gene:
BTD
Variant:
c.1336G>C
(p.Asp446His)
rsID: rs13078881
Ref Allele: G
Alt Allele: C
Freq: 2.5667%uncommon
CADD: 23.3
ClinVar Submissions (15)
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
Low clinical importance, pathogenic — This variant is implicated in partial and profound biotinidase deficiency. Alone, this variant is estimated to have a 52% loss of enzymatic activity. This variant is often found with A171T, and together they are reported to cause profound deficiency. Notably there is a report of asymptomatic double-mutant adults, so symptoms may have variable penetrance. This variant is found compound heterozygously with more serious mutations in cases of partial biotinidase deficiency.
Expert Reviewed Clinically Significant Conflicting/Uncertain
Hetero
Gene:
ACADS
Variant:
c.511C>T
(p.Arg171Trp)
rsID: rs1800556
Ref Allele: C
Alt Allele: T
Freq: 2.8686%uncommon
CADD: 22
ClinVar Submissions (7)
Most infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria are reported. Thus, SCADD is now viewed as a biochemical phenotype rather than a disease. A broad range of clinical findings was originally reported in those with confirmed SCADD, including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported. In a large series of affected individuals detected on metabolic evaluation for developmental delay, 20% had failure to thrive, feeding difficulties, and hypotonia; 22% had seizures; and 30% had hypotonia without seizures. In contrast, the majority of infants with SCADD have been detected by expanded newborn screening, and the great majority of these infants remain asymptomatic. As with other fatty acid oxidation deficiencies, characteristic biochemical findings of SCADD may be absent except during times of physiologic stress such as fasting and illness. A diagnosis of SCADD based on clinical findings should not preclude additional testing to look for other causes.
Last Evaluated: Jun 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 12:120737875
OMIM Allelic Variant: 606885.0006
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 12:120737875
OMIM Allelic Variant: 606885.0006
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 12:120737875
OMIM Allelic Variant: 606885.0006
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
GAA
Variant:
c.2065G>A
(p.Glu689Lys)
rsID: rs1800309
Ref Allele: G
Alt Allele: A
Freq: 4.5426%uncommon
CADD: 18.3
ClinVar Submissions (8)
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Low clinical importance, Uncertain benign — This is also known as the GAA*4 allozyme is frequent in the Asian population and appears to have somewhat reduced enzyme activity. Kroos et al. rule out pathogenic effect.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
IQCB1
Variant:
c.1178T>A
(p.Ile393Asn)
rsID: rs1141528
Ref Allele: A
Alt Allele: T
Freq: 9.062%
CADD: 23.1
ClinVar Submissions (4)
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:121788384
Senior-Loken syndrome is an autosomal recessive disease with the main features of nephronophthisis (NPHP; see 256100) and Leber congenital amaurosis (see 204000). Mutations in some of the same genes that cause nephronophthisis (see 256100) cause Senior-Loken syndrome. Genetic Heterogeneity of Senior-Loken Syndrome Other forms of SLSN include SLSN4 (606996), caused by mutation in the NPHP4 gene (607215) on chromosome 1p36; SLSN5 (609254), caused by mutation in the NPHP5 gene (IQCB1; 609237) on chromosome 3q13; SLSN6 (610189), caused by mutation in the NPHP6 gene (CEP290; 610142) on chromosome 12q21; SLSN7 (613615), caused by mutation in the SDCCAG8 gene (613524) on chromosome 1q43; SLSN8 (616307), caused by mutation in the WDR19 gene (608151) on chromosome 4p14; and SLSN9 (616629), caused by mutation in the TRAF3IP1 gene (607380) on chromosome 2q37. Another form of SLSN, SLSN3 (606995), has been mapped to a locus on chromosome 3q22, overlapping the NPHP3 locus (604387).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:121788384
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:121788384
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
HFE
Variant:
c.187C>G
(p.His63Asp)
rsID: rs1799945
Ref Allele: C
Alt Allele: G
Freq: 10.1156%
CADD: 12.32
ClinVar Submissions (12)
HFE hemochromatosis is characterized by inappropriately high absorption of iron by the small intestinal mucosa. The phenotypic spectrum of HFE hemochromatosis includes: Persons with clinical HFE hemochromatosis, in whom manifestations of end-organ damage secondary to iron overload are present; Individuals with biochemical HFE hemochromatosis, in whom transferrin-iron saturation is increased and the only evidence of iron overload is increased serum ferritin concentration; and Non-expressing p.Cys282Tyr homozygotes, in whom neither clinical manifestations of HFE hemochromatosis nor iron overload are present. Clinical HFE hemochromatosis is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and anterior pituitary gland. In untreated individuals, early symptoms include: abdominal pain, weakness, lethargy, weight loss, arthralgias, diabetes mellitus; and increased risk of cirrhosis when the serum ferritin is higher than 1,000 ng/mL. Other findings may include progressive increase in skin pigmentation, congestive heart failure, and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE hemochromatosis is more common in men than women.
Last Evaluated: Jul 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 12
Clinical Significance: Pathogenic, other, risk factor
Assembly: GRCh38
Chromosome/Position: 6:26090951
OMIM Allelic Variant: 613609.0002
HFE hemochromatosis is characterized by inappropriately high absorption of iron by the small intestinal mucosa. The phenotypic spectrum of HFE hemochromatosis includes: Persons with clinical HFE hemochromatosis, in whom manifestations of end-organ damage secondary to iron overload are present; Individuals with biochemical HFE hemochromatosis, in whom transferrin-iron saturation is increased and the only evidence of iron overload is increased serum ferritin concentration; and Non-expressing p.Cys282Tyr homozygotes, in whom neither clinical manifestations of HFE hemochromatosis nor iron overload are present. Clinical HFE hemochromatosis is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and anterior pituitary gland. In untreated individuals, early symptoms include: abdominal pain, weakness, lethargy, weight loss, arthralgias, diabetes mellitus; and increased risk of cirrhosis when the serum ferritin is higher than 1,000 ng/mL. Other findings may include progressive increase in skin pigmentation, congestive heart failure, and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE hemochromatosis is more common in men than women.
Last Evaluated: Jul 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 12
Clinical Significance: Pathogenic, other, risk factor
Assembly: GRCh38
Chromosome/Position: 6:26090951
OMIM Allelic Variant: 613609.0002
Last Evaluated: Jul 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 12
Clinical Significance: Pathogenic, other, risk factor
Assembly: GRCh38
Chromosome/Position: 6:26090951
OMIM Allelic Variant: 613609.0002
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 12
Clinical Significance: Pathogenic, other, risk factor
Assembly: GRCh38
Chromosome/Position: 6:26090951
OMIM Allelic Variant: 613609.0002
Low clinical importance, Uncertain pathogenic — There have been some hypotheses that this variant contributes to causing hereditary hemochromatosis, possibly as a compound heterozygote, but some others treat it as a polymorphism. Cys282Tyr is the classic causal variant and itself has very low penetrance. Mouse studies indicates this variant has a similar but weaker effect; if it has any effect at all its penetrance may be quite low and/or require modifier alleles.
Expert Reviewed Clinically Significant Pathogenic, other, risk factor
Hetero
Gene:
MBL2
Variant:
c.161G>A
(p.Gly54Asp)
rsID: rs1800450
Ref Allele: C
Alt Allele: T
Freq: 11.4233%
CADD: 23.7
ClinVar Submissions (2)
Mannose-binding lectin (MBL) deficiency, defined as MBL protein level of less than 100 ng/ml, is present in about 5% of people of European descent and in about 10% of sub-Saharan Africans. Most MBL-deficient adults appear healthy, but low levels of MBL are associated with increased risk of infection in toddlers, in cancer patients undergoing chemotherapy, and in organ-transplant patients receiving immunosuppressive drugs, particularly recipients of liver transplants (review by Degn et al., 2011). MBL is a soluble molecule that can activate the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system (summary by Garcia-Laorden et al., 2008). Genetic Heterogeneity of Lectin Complement Activation Pathway Defects See also LCAPD2 (613791), caused by variation in the MASP2 gene (605102) on chromosome 1p36, and LCAPD3 (613860), caused by variation in the FCN3 gene (604973) on chromosome 1p36.
Last Evaluated: Oct 01, 2004
Review Status: no assertion criteria provided
Number of Submitters: 2
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 10:52771475
OMIM Allelic Variant: 154545.0001
Low clinical importance, Likely pathogenic — This variant is associated with mannose binding protein deficiency which leads to impaired complement system immune response to mannose-rich pathogens. Patients homozygous for this allele or compound heterozygous are likely to have increased susceptibility to infection, but Hellemann et al. report heterosis for intensive care outcomes in heterozygous subjects. The wild-type version of this gene is known as variant allele A, while this is called variant allele B. See R52C (variant D) and G57E (variant C).
Clinically Significant Pathogenic
Hetero
Gene:
FUT6
Variant:
c.739G>A
(p.Glu247Lys)
rsID: rs17855739
Ref Allele: C
Alt Allele: T
Freq: 12.4745%
CADD: 23.3
ClinVar Submissions (2)
Last Evaluated: Mar 18, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 19:5831829
OMIM Allelic Variant: 136836.0001
Clinically Significant Conflicting/Uncertain
Homo
Gene:
GNPAT
Variant:
c.1556A>G
(p.Asp519Gly)
rsID: rs11558492
Ref Allele: A
Alt Allele: G
Freq: 16.5934%
CADD: 22.1
ClinVar Submissions (6)
An autosomal recessive form of CHONDRODYSPLASIA PUNCTATA characterized by defective plasmalogen biosynthesis and impaired peroxisomes. Patients have shortened proximal limbs and severely disturbed endochondral bone formation. The metabolic defects associated with the impaired peroxisomes are present only in the rhizomelic form of chondrodysplasia punctata. (From Scriver et al, Metabolic Basis of Inherited Disease, 6th ed, p1497)
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:231272345
OMIM Allelic Variant: 602744.0006
Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 (215100) is the most frequent form of RCDP (summary by Wanders and Waterham, 2005). Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 is classified as a single peroxisome enzyme deficiency (Waterham and Ebberink, 2012). For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see 215100.
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:231272345
OMIM Allelic Variant: 602744.0006
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:231272345
OMIM Allelic Variant: 602744.0006
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:231272345
OMIM Allelic Variant: 602744.0006
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
STOX1
Variant:
c.1824A>C
(p.Glu608Asp)
rsID: rs10509305
Ref Allele: A
Alt Allele: C
Freq: 16.599%
CADD: 0.003
ClinVar Submissions (1)
Preeclampsia is a complication of pregnancy in which affected women develop high blood pressure (hypertension); they can also have abnormally high levels of protein in their urine (proteinuria). This condition usually occurs in the last few months of pregnancy and often requires early delivery of the infant. However, this condition can also appear shortly after giving birth (postpartum preeclampsia).Many women with mild preeclampsia do not feel ill, and the condition is often first detected through blood pressure and urine testing in their doctor's office. In addition to hypertension and proteinuria, signs and symptoms of preeclampsia can include excessive swelling (edema) of the face or hands and a weight gain of more than 3 to 5 pounds in a week due to fluid retention. Affected women may also experience headaches, dizziness, irritability, shortness of breath, a decrease in urination, upper abdominal pain, and nausea or vomiting. Vision changes may develop, including flashing lights or spots, increased sensitivity to light (photophobia), blurry vision, or temporary blindness.In many cases, symptoms of preeclampsia go away within a few days after the baby is born. In severe cases, however, preeclampsia can damage the mother's organs, such as the heart, liver, and kidneys, and can lead to life-threatening complications. Extremely high blood pressure in the mother can cause bleeding in the brain (hemorrhagic stroke). The effects of high blood pressure on the brain (hypertensive encephalopathy) may also result in seizures. If seizures occur, the condition is considered to have worsened to eclampsia, which can result in coma. About 1 in 200 women with untreated preeclampsia develop eclampsia. Eclampsia can also develop without any obvious signs of preeclampsia.Between 10 and 20 percent of women with severe preeclampsia develop another potentially life-threatening complication called HELLP syndrome. HELLP stands for hemolysis (premature red blood cell breakdown), elevated liver enzyme levels, and low platelets (cell fragments involved in blood clotting), which are the key features of this condition.Severe preeclampsia can also affect the fetus, with impairment of blood and oxygen flow leading to growth problems or stillbirth. Infants delivered early due to preeclampsia may have complications associated with prematurity, such as breathing problems caused by underdeveloped lungs.Women who have had preeclampsia have approximately twice the lifetime risk of heart disease and stroke than do women in the general population. Researchers suggest that preeclampsia, heart disease, and stroke may share common risk factors. Women who have health conditions such as obesity, hypertension, heart disease, diabetes, or kidney disease before they become pregnant have an increased risk of developing preeclampsia. Preeclampsia is most likely to occur in a woman's first pregnancy, although it can occur in subsequent pregnancies, particularly in women with other health conditions.
Last Evaluated: May 01, 2005
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 10:68885620
OMIM Allelic Variant: 609397.0002
Clinically Significant Pathogenic
Hetero
Gene:
CST3
Variant:
c.73G>A
(p.Ala25Thr)
rsID: rs1064039
Ref Allele: C
Alt Allele: T
Freq: 19.1769%
CADD: 7.532
ClinVar Submissions (1)
Age-related macular degeneration is an eye disease that is a leading cause of vision loss in older people in developed countries. The vision loss usually becomes noticeable in a person's sixties or seventies and tends to worsen over time.Age-related macular degeneration mainly affects central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. The vision loss in this condition results from a gradual deterioration of light-sensing cells in the tissue at the back of the eye that detects light and color (the retina). Specifically, age-related macular degeneration affects a small area near the center of the retina, called the macula, which is responsible for central vision. Side (peripheral) vision and night vision are generally not affected, but reduced dim light (scotopic) vision often occurs in the early stages of the disease.Researchers have described two major types of age-related macular degeneration, known as the dry form and the wet form. The dry form is much more common, accounting for 85 to 90 percent of all cases of age-related macular degeneration. It is characterized by a buildup of yellowish deposits called drusen beneath the retina and vision loss that worsens slowly over time. The condition typically affects vision in both eyes, although vision loss often occurs in one eye before the other.The wet form of age-related macular degeneration is associated with severe vision loss that can worsen rapidly. This form of the condition is characterized by the growth of abnormal, fragile blood vessels underneath the macula. These vessels leak blood and fluid, which damages the macula and makes central vision appear blurry and distorted.
Last Evaluated: Feb 01, 2002
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 20:23637790
OMIM Allelic Variant: 604312.0002
Insufficiently evaluated pathogenic — Associated with age-related macular degeneration and alzheimer's disease.
Clinically Significant Pathogenic
Hetero
Gene:
RPGRIP1
Variant:
c.1639G>T
(p.Ala547Ser)
rsID: rs10151259
Ref Allele: G
Alt Allele: T
Freq: 20.3834%
CADD: 23.1
ClinVar Submissions (7)
Last Evaluated: Oct 21, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:21321881
OMIM Allelic Variant: 605446.0006
Cone-rod dystrophy is a group of related eye disorders that causes vision loss, which becomes more severe over time. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye. In people with cone-rod dystrophy, vision loss occurs as the light-sensing cells of the retina gradually deteriorate.The first signs and symptoms of cone-rod dystrophy, which often occur in childhood, are usually decreased sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). These features are typically followed by impaired color vision (dyschromatopsia), blind spots (scotomas) in the center of the visual field, and partial side (peripheral) vision loss. Over time, affected individuals develop night blindness and a worsening of their peripheral vision, which can limit independent mobility. Decreasing visual acuity makes reading increasingly difficult and most affected individuals are legally blind by mid-adulthood. As the condition progresses, individuals may develop involuntary eye movements (nystagmus).There are more than 30 types of cone-rod dystrophy, which are distinguished by their genetic cause and their pattern of inheritance: autosomal recessive, autosomal dominant, and X-linked. Additionally, cone-rod dystrophy can occur alone without any other signs and symptoms or it can occur as part of a syndrome that affects multiple parts of the body.
Last Evaluated: Oct 21, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:21321881
OMIM Allelic Variant: 605446.0006
Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). Genetic Heterogeneity of Leber Congenital Amaurosis LCA2 (204100) is caused by mutation in the RPE65 gene (RPE65; 180069) on chromosome 1p31. LCA3 (604232) is caused by mutation in the SPATA7 gene (609868) on chromosome 14q31. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14. LCA6 (613826) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. LCA7 (613829) is caused by mutation in the CRX gene (602225) on chromosome 19q13. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31. LCA9 (608553) is caused by mutation in the NMNAT1 gene (608700) on chromosome 1p36. LCA10 (611755) is caused by mutation in the CEP290 gene (610142) on chromosome 12q21 and may account for as many as 21% of cases of LCA. LCA11 (613837) is caused by mutation in the IMPDH1 gene (146690) on chromosome 7q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q32. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. LCA17 (615360) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. LCA18 (see 608133) is caused by mutation in the PRPH2 gene (179605) on chromosome 6p21. Perrault et al. (1999) provided a review of Leber congenital amaurosis, with emphasis on genetic heterogeneity. Wiszniewski et al. (2011) analyzed 13 known LCA genes in 60 LCA probands, and identified homozygous or compound heterozygous mutations in 42 (70%). In addition, a third disease-associated mutant allele at a second locus was identified in 7 (12%) of the 60 patients. Wiszniewski et al. (2011) stated that the significance of the third mutated allele was unknown, but suggested that mutational load might be important to penetrance of the LCA phenotype. Because LCA manifests very early in life and results in profound vision loss, patients with mutations in other syndromic or nonsyndromic eye disease genes may receive an initial diagnosis of LCA, prior to development of syndromic features or before more thorough phenotyping can be performed (see, e.g., Senior-Loken syndrome-5, 609254).
Last Evaluated: Oct 21, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:21321881
OMIM Allelic Variant: 605446.0006
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 21, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:21321881
OMIM Allelic Variant: 605446.0006
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 21, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:21321881
OMIM Allelic Variant: 605446.0006
Low clinical importance, Uncertain benign — Probably benign. Implicated in causing autosomal recessive cone-rod dystrophy, but a later report found the same incidence in controls and concludes it is not causal.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
FGFR4
Variant:
c.1162G>A
(p.Gly388Arg)
rsID: rs351855
Ref Allele: G
Alt Allele: A
Freq: 26.6748%
CADD: 25.6
ClinVar Submissions (1)
Last Evaluated: Feb 01, 2002
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 5:177093242
OMIM Allelic Variant: 134935.0001
Insufficiently evaluated pharmacogenetic — Possible association with sensitivity to cisplatin; poor outcome with cyclophosphamide, fluoruracil, methotextrate and tamoxifen.
Clinically Significant Pathogenic
Hetero
Gene:
GCDH
Variant:
c.852+223C>T
rsID: rs11085825
Ref Allele: C
Alt Allele: T
Freq: 30.6846%
CADD: 1.467
ClinVar Submissions (1)
Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (Goodman et al., 1995). Hedlund et al. (2006) provided a detailed review of the clinical and biochemical aspects of glutaric acidemia type I.
Last Evaluated: Dec 08, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: 19:12896644
Clinically Significant Likely pathogenic
Hetero
Gene:
GCDH
Variant:
c.*288G>T
rsID: rs9384
Ref Allele: G
Alt Allele: T
Freq: 33.4719%
CADD: 1.464
ClinVar Submissions (2)
An increased concentration of glutaric acid in the blood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:12899829
Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (Goodman et al., 1995). Hedlund et al. (2006) provided a detailed review of the clinical and biochemical aspects of glutaric acidemia type I.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:12899829
Clinically Significant Benign
Hetero
Gene:
GATA4
Variant:
c.*1256A>T
rsID: rs12458
Ref Allele: A
Alt Allele: T
Freq: 35.6221%
CADD: 2.229
ClinVar Submissions (1)
Critical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.Although babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.Some people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.Each of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.
Last Evaluated: Jan 07, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 8:11759731
Clinically Significant Pathogenic
Hetero
Gene:
CCDC170
Variant:
c.1810G>A
(p.Val604Ile)
rsID: rs6929137
Ref Allele: G
Alt Allele: A
Freq: 37.1743%
CADD: 4.328
ClinVar Submissions (1)
Estrogen resistance (ESTRR) is characterized by absence of puberty with elevated estradiol and gonadotropic hormones, as well as markedly delayed bone maturation. Female patients show absent breast development, small uterus, and enlarged multicystic ovaries; male patients may show small testes (Bernard et al., 2017). Some patients exhibit continued growth into adulthood (Smith et al., 1994).
Last Evaluated: Mar 01, 2014
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: 6:151615542
Clinically Significant Likely pathogenic
Hetero
Gene:
ACTN3
Variant:
c.1729C>T
(p.Arg577Ter)
rsID: rs1815739
Ref Allele: C
Alt Allele: T
Freq: 37.4841%
CADD: 40
ClinVar Submissions (1)
Last Evaluated: Oct 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, Affects
Assembly: GRCh38
Chromosome/Position: 11:66560624
OMIM Allelic Variant: 102574.0001
Last Evaluated: Oct 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, Affects
Assembly: GRCh38
Chromosome/Position: 11:66560624
OMIM Allelic Variant: 102574.0001
Last Evaluated: Oct 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, Affects
Assembly: GRCh38
Chromosome/Position: 11:66560624
OMIM Allelic Variant: 102574.0001
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
GATA4
Variant:
c.1147-107A>G
rsID: rs745379
Ref Allele: A
Alt Allele: G
Freq: 38.0105%
CADD: 2.248
ClinVar Submissions (1)
Critical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.Although babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.Some people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.Each of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.
Last Evaluated: Jan 07, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 8:11758186
Clinically Significant Pathogenic
Hetero
Gene:
UROS
Variant:
c.-219C>A
rsID: rs4385801
Ref Allele: G
Alt Allele: T
Freq: 40.7015%
CADD: 5.844
ClinVar Submissions (2)
Congenital erythropoietic porphyria (CEP) is characterized in most individuals by severe cutaneous photosensitivity with blistering and increased friability of the skin over light-exposed areas. Onset in most affected individuals occurs at birth or early infancy. The first manifestation is often pink to dark red discoloration of the urine. Hemolytic anemia is common and can range from mild to severe, with some affected individuals requiring chronic blood transfusions. Porphyrin deposition may lead to corneal ulcers and scarring, reddish-brown discoloration of the teeth (erythrodontia), and mild bone loss and/or expansion of the bone marrow. The phenotypic spectrum, however, is broad and ranges from non-immune hydrops fetalis in utero to late-onset disease with only mild cutaneous manifestations in adulthood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:125823221
Clinically Significant Benign
Hetero
Gene:
PRSS1
Variant:
c.47C>T
(p.Ala16Val)
rsID: rs202003805
Ref Allele: C
Alt Allele: T
Freq: 40.938%
CADD: 0.048
ClinVar Submissions (6)
A disorder characterized by recurrent episodes of pancreatitis that start at a young age. It is caused by mutations in the PRSS1 or SPINK1 genes. Patients are at a high risk of developing pancreatic carcinoma.
Last Evaluated: Apr 15, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:142750561
A recurrent form of pancreatitis. [HPO:probinson]
Last Evaluated: Apr 15, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:142750561
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 15, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:142750561
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
CCDC170
Variant:
g.151627231G>A
rsID: rs2046210
Ref Allele: G
Alt Allele: A
Freq: 42.4017%
CADD: 0.277
ClinVar Submissions (1)
Estrogen resistance (ESTRR) is characterized by absence of puberty with elevated estradiol and gonadotropic hormones, as well as markedly delayed bone maturation. Female patients show absent breast development, small uterus, and enlarged multicystic ovaries; male patients may show small testes (Bernard et al., 2017). Some patients exhibit continued growth into adulthood (Smith et al., 1994).
Last Evaluated: Mar 01, 2014
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: 6:151627231
Expert Reviewed Clinically Significant Likely pathogenic
Hetero
Gene:
CYP4V2
Variant:
c.64C>G
(p.Leu22Val)
rsID: rs1055138
Ref Allele: C
Alt Allele: G
Freq: 45.4383%
CADD: 3.733
ClinVar Submissions (6)
Bietti crystalline dystrophy (BCD) is a chorioretinal degeneration characterized by the presence of yellow-white crystals and/or complex lipid deposits in the retina and (to a variable degree) the cornea. Progressive atrophy and degeneration of the retinal pigment epithelium (RPE) / choroid lead to symptoms similar to those of other forms of retinal degeneration that fall under the category of retinitis pigmentosa and allied disorders, namely: reduced visual acuity, poor night vision, abnormal retinal electrophysiology, visual field loss, and often impaired color vision. Marked asymmetry between eyes is not uncommon. Onset is typically during the second to third decade of life, but ranges from the early teenage years to beyond the third decade. With time, loss of peripheral visual field, central acuity, or both result in legal blindness in most if not all affected individuals.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
Clinically Significant Benign
Hetero
Gene:
COL4A4
Variant:
c.3979G>A
(p.Val1327Met)
rsID: rs2229813
Ref Allele: C
Alt Allele: T
Freq: 46.2371%
CADD: 2.045
ClinVar Submissions (6)
Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities.People with Alport syndrome experience progressive loss of kidney function. Almost all affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys. Many people with Alport syndrome also develop high levels of protein in their urine (proteinuria). The kidneys become less able to function as this condition progresses, resulting in end-stage renal disease (ESRD).People with Alport syndrome frequently develop sensorineural hearing loss, which is caused by abnormalities of the inner ear, during late childhood or early adolescence. Affected individuals may also have misshapen lenses in the eyes (anterior lenticonus) and abnormal coloration of the light-sensitive tissue at the back of the eye (retina). These eye abnormalities seldom lead to vision loss.Significant hearing loss, eye abnormalities, and progressive kidney disease are more common in males with Alport syndrome than in affected females.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:227028004
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:227028004
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:227028004
Clinically Significant Benign
Hetero
Gene:
CCR5
Variant:
c.-301+246A>G
rsID: rs1799987
Ref Allele: A
Alt Allele: G
Freq: 49.3884%
CADD: 2.992
ClinVar Submissions (1)
Last Evaluated: Jul 08, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, protective
Assembly: GRCh38
Chromosome/Position: 3:46370444
OMIM Allelic Variant: 601373.0006
Last Evaluated: Jul 08, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, protective
Assembly: GRCh38
Chromosome/Position: 3:46370444
OMIM Allelic Variant: 601373.0006
Last Evaluated: Jul 08, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, protective
Assembly: GRCh38
Chromosome/Position: 3:46370444
OMIM Allelic Variant: 601373.0006
Clinically Significant Conflicting/Uncertain
Hetero
Below are rare variants (frequency less than 1%) that were submitted to ClinVar. The data presented has no guarantees of reporting accuracy. Heterozygous variants are reported as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
NPHP4
Variant:
c.3723C>T
(p.Val1241=)
rsID: rs375485412
Ref Allele: G
Alt Allele: A
Freq: 0.0016%rare
CADD: 0.279
ClinVar Submissions (1)
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:5865195
Senior-Loken syndrome is an autosomal recessive disease with the main features of nephronophthisis (NPHP; see 256100) and Leber congenital amaurosis (see 204000). Mutations in some of the same genes that cause nephronophthisis (see 256100) cause Senior-Loken syndrome. Genetic Heterogeneity of Senior-Loken Syndrome Other forms of SLSN include SLSN4 (606996), caused by mutation in the NPHP4 gene (607215) on chromosome 1p36; SLSN5 (609254), caused by mutation in the NPHP5 gene (IQCB1; 609237) on chromosome 3q13; SLSN6 (610189), caused by mutation in the NPHP6 gene (CEP290; 610142) on chromosome 12q21; SLSN7 (613615), caused by mutation in the SDCCAG8 gene (613524) on chromosome 1q43; SLSN8 (616307), caused by mutation in the WDR19 gene (608151) on chromosome 4p14; and SLSN9 (616629), caused by mutation in the TRAF3IP1 gene (607380) on chromosome 2q37. Another form of SLSN, SLSN3 (606995), has been mapped to a locus on chromosome 3q22, overlapping the NPHP3 locus (604387).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:5865195
Conflicting/Uncertain
Hetero
Gene:
SCN2A
Variant:
c.3210C>T
(p.Asp1070=)
rsID: rs187731029
Ref Allele: C
Alt Allele: T
Freq: 0.0032%rare
CADD: 1.676
ClinVar Submissions (3)
Last Evaluated: Dec 03, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:165354482
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 03, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:165354482
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 03, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:165354482
Conflicting/Uncertain
Hetero
Gene:
COL6A3
Variant:
c.9394C>T
(p.Pro3132Ser)
rsID: rs147533489
Ref Allele: G
Alt Allele: A
Freq: 0.0032%rare
CADD: 0.067
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 04, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:237325659
Conflicting/Uncertain
Hetero
Gene:
PLEC
Variant:
c.3566G>A
(p.Arg1189Gln)
rsID: rs368280705
Ref Allele: C
Alt Allele: T
Freq: 0.0032%rare
CADD: 21.5
ClinVar Submissions (2)
Epidermolysis bullosa simplex with muscular dystrophy is an autosomal recessive disorder characterized by early childhood onset of progressive muscular dystrophy and blistering skin changes (Fine et al., 1989). Fine et al. (1991) reported a revised classification of the subtypes of inherited epidermolysis bullosa. In reports of 2 consensus meetings on EB, Fine et al. (2000, 2008) referred to EB with muscular dystrophy due to PLEC1 mutations as a form of basal simplex EB. Fine et al. (2000, 2008) also eliminated the term 'hemidesmosomal,' which had previously been proposed for this entity (Uitto et al., 1997) because ultrastructural analysis can demonstrate tissue abnormalities of the hemidesmosomes.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143927681
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143927681
EBSPA is an autosomal recessive genodermatosis characterized by severe skin blistering at birth and congenital pyloric atresia. Death usually occurs in infancy. In reports of 2 consensus meetings for EB, Fine et al. (2000, 2008) considered EBSPA to be a 'basal' form of simplex EB because the electron microscopy shows that skin cleavage occurs in the lower basal level of the keratinocyte, just above the hemidesmosome. There is often decreased integration of keratin filaments with hemidesmosomes.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143927681
Epidermolysis bullosa simplex is one of a group of genetic conditions called epidermolysis bullosa that cause the skin to be very fragile and to blister easily. Blisters and areas of skin loss (erosions) occur in response to minor injury or friction, such as rubbing or scratching. Epidermolysis bullosa simplex is one of the major forms of epidermolysis bullosa. The signs and symptoms of this condition vary widely among affected individuals. Blistering primarily affects the hands and feet in mild cases, and the blisters usually heal without leaving scars. Severe cases of this condition involve widespread blistering that can lead to infections, dehydration, and other medical problems. Severe cases may be life-threatening in infancy.Researchers have identified four major types of epidermolysis bullosa simplex. Although the types differ in severity, their features overlap significantly, and they are caused by mutations in the same genes. Most researchers now consider the major forms of this condition to be part of a single disorder with a range of signs and symptoms.The mildest form of epidermolysis bullosa simplex, known as the localized type (formerly called the Weber-Cockayne type), is characterized by skin blistering that begins anytime between childhood and adulthood and is usually limited to the hands and feet. Later in life, skin on the palms of the hands and soles of the feet may thicken and harden (hyperkeratosis).The Dowling-Meara type is the most severe form of epidermolysis bullosa simplex. Extensive, severe blistering can occur anywhere on the body, including the inside of the mouth, and blisters may appear in clusters. Blistering is present from birth and tends to improve with age. Affected individuals also experience abnormal nail growth and hyperkeratosis of the palms and soles.Another form of epidermolysis bullosa simplex, known as the other generalized type (formerly called the Koebner type), is associated with widespread blisters that appear at birth or in early infancy. The blistering tends to be less severe than in the Dowling-Meara type.Epidermolysis bullosa simplex with mottled pigmentation is characterized by patches of darker skin on the trunk, arms, and legs that fade in adulthood. This form of the disorder also involves skin blistering from early infancy, hyperkeratosis of the palms and soles, and abnormal nail growth.In addition to the four major types described above, researchers have identified another skin condition related to epidermolysis bullosa simplex, which they call the Ogna type. It is caused by mutations in a gene that is not associated with the other types of epidermolysis bullosa simplex. It is unclear whether the Ogna type is a subtype of epidermolysis bullosa simplex or represents a separate form of epidermolysis bullosa.Several other variants of epidermolysis bullosa simplex have been proposed, but they appear to be very rare.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143927681
Autosomal recessive limb-girdle muscular dystrophy-17 is characterized by early childhood onset of proximal muscle weakness and atrophy without skin involvement. One family has shown rapid progression of the disorder in adolescence (summary by Gundesli et al., 2010). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143927681
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143927681
Conflicting/Uncertain
Hetero
Gene:
PLEC
Variant:
c.1004C>T
(p.Pro335Leu)
rsID: rs781813266
Ref Allele: G
Alt Allele: A
Freq: 0.0032%rare
CADD: 26.9
ClinVar Submissions (2)
Epidermolysis bullosa simplex with muscular dystrophy is an autosomal recessive disorder characterized by early childhood onset of progressive muscular dystrophy and blistering skin changes (Fine et al., 1989). Fine et al. (1991) reported a revised classification of the subtypes of inherited epidermolysis bullosa. In reports of 2 consensus meetings on EB, Fine et al. (2000, 2008) referred to EB with muscular dystrophy due to PLEC1 mutations as a form of basal simplex EB. Fine et al. (2000, 2008) also eliminated the term 'hemidesmosomal,' which had previously been proposed for this entity (Uitto et al., 1997) because ultrastructural analysis can demonstrate tissue abnormalities of the hemidesmosomes.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143934832
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143934832
EBSPA is an autosomal recessive genodermatosis characterized by severe skin blistering at birth and congenital pyloric atresia. Death usually occurs in infancy. In reports of 2 consensus meetings for EB, Fine et al. (2000, 2008) considered EBSPA to be a 'basal' form of simplex EB because the electron microscopy shows that skin cleavage occurs in the lower basal level of the keratinocyte, just above the hemidesmosome. There is often decreased integration of keratin filaments with hemidesmosomes.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143934832
Epidermolysis bullosa simplex is one of a group of genetic conditions called epidermolysis bullosa that cause the skin to be very fragile and to blister easily. Blisters and areas of skin loss (erosions) occur in response to minor injury or friction, such as rubbing or scratching. Epidermolysis bullosa simplex is one of the major forms of epidermolysis bullosa. The signs and symptoms of this condition vary widely among affected individuals. Blistering primarily affects the hands and feet in mild cases, and the blisters usually heal without leaving scars. Severe cases of this condition involve widespread blistering that can lead to infections, dehydration, and other medical problems. Severe cases may be life-threatening in infancy.Researchers have identified four major types of epidermolysis bullosa simplex. Although the types differ in severity, their features overlap significantly, and they are caused by mutations in the same genes. Most researchers now consider the major forms of this condition to be part of a single disorder with a range of signs and symptoms.The mildest form of epidermolysis bullosa simplex, known as the localized type (formerly called the Weber-Cockayne type), is characterized by skin blistering that begins anytime between childhood and adulthood and is usually limited to the hands and feet. Later in life, skin on the palms of the hands and soles of the feet may thicken and harden (hyperkeratosis).The Dowling-Meara type is the most severe form of epidermolysis bullosa simplex. Extensive, severe blistering can occur anywhere on the body, including the inside of the mouth, and blisters may appear in clusters. Blistering is present from birth and tends to improve with age. Affected individuals also experience abnormal nail growth and hyperkeratosis of the palms and soles.Another form of epidermolysis bullosa simplex, known as the other generalized type (formerly called the Koebner type), is associated with widespread blisters that appear at birth or in early infancy. The blistering tends to be less severe than in the Dowling-Meara type.Epidermolysis bullosa simplex with mottled pigmentation is characterized by patches of darker skin on the trunk, arms, and legs that fade in adulthood. This form of the disorder also involves skin blistering from early infancy, hyperkeratosis of the palms and soles, and abnormal nail growth.In addition to the four major types described above, researchers have identified another skin condition related to epidermolysis bullosa simplex, which they call the Ogna type. It is caused by mutations in a gene that is not associated with the other types of epidermolysis bullosa simplex. It is unclear whether the Ogna type is a subtype of epidermolysis bullosa simplex or represents a separate form of epidermolysis bullosa.Several other variants of epidermolysis bullosa simplex have been proposed, but they appear to be very rare.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143934832
Autosomal recessive limb-girdle muscular dystrophy-17 is characterized by early childhood onset of proximal muscle weakness and atrophy without skin involvement. One family has shown rapid progression of the disorder in adolescence (summary by Gundesli et al., 2010). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143934832
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:143934832
Conflicting/Uncertain
Hetero
Gene:
NF2
Variant:
c.1000-7C>G
rsID: rs776237839
Ref Allele: C
Alt Allele: G
Freq: 0.0032%rare
CADD: 0.162
ClinVar Submissions (2)
Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas. Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings (retinal hamartoma, thickened optic nerves, cortical wedge cataracts, third cranial nerve palsy) may be the first manifestations. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy or hand/foot drop.
Last Evaluated: Jun 14, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:29671819
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:29671819
Conflicting/Uncertain
Hetero
Gene:
LDB3
Variant:
c.1071T>A
(p.Pro357=)
rsID: rs143823978
Ref Allele: T
Alt Allele: A
Freq: 0.0072%rare
CADD: 2.096
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 19, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:86706705
Likely benign
Hetero
Gene:
FOXP1
Variant:
c.13T>C
(p.Ser5Pro)
rsID: rs762898505
Ref Allele: A
Alt Allele: G
Freq: 0.0104%rare
CADD: 28.9
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 29, 2014
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:71198369
Conflicting/Uncertain
Hetero
Gene:
DOK7
Variant:
c.189C>T
(p.Cys63=)
rsID: rs372989037
Ref Allele: C
Alt Allele: T
Freq: 0.0135%rare
CADD: 8.163
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:3473494
Likely benign
Hetero
Gene:
GNE
Variant:
c.*2415T>A
rsID: rs143569888
Ref Allele: A
Alt Allele: T
Freq: 0.0151%rare
CADD: 13.85
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:36214950
GNE-related myopathy, also known as inclusion body myopathy 2, is characterized by slowly progressive distal muscle weakness that begins in the late teens to early adult years with gait disturbance and foot drop secondary to anterior tibialis muscle weakness. Weakness eventually includes the hand and thigh muscles but commonly spares the quadriceps muscles, even in advanced disease. Affected individuals are usually wheelchair bound about 20 years after onset. If quadriceps sparing is incomplete, loss of ambulation tends to occur earlier.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:36214950
Sialuria is a rare inborn error of metabolism in which excessive free sialic acid is synthesized. Clinical features include hepatosplenomegaly, coarse facial features, and varying degrees of developmental delay (summary by Enns et al., 2001).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:36214950
Likely benign
Hetero
Gene:
STIM1
Variant:
c.1128C>T
(p.Ala376=)
rsID: rs200375470
Ref Allele: C
Alt Allele: T
Freq: 0.0151%rare
CADD: 11.45
ClinVar Submissions (1)
Immunodeficiency-10 is an autosomal recessive primary immunodeficiency characterized by onset of recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta (summary by Parry et al., 2016).
Last Evaluated: Dec 12, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:4082342
Tubular aggregates in muscle, first described by Engel (1964), are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. They are a nonspecific pathologic finding that may occur in a variety of circumstances, including alcohol- and drug-induced myopathies, exercise-induced cramps or muscle weakness, and inherited myopathies. Tubular aggregates are derived from the sarcoplasmic reticulum (Salviati et al., 1985) and are believed to represent an adaptive mechanism aimed at regulating an increased intracellular level of calcium in order to prevent the muscle fibers from hypercontraction and necrosis (Martin et al., 1997; Muller et al., 2001). Genetic Heterogeneity of Tubular Aggregate Myopathy See also TAM2 (615883), caused by mutation in the ORAI1 gene (610277) on chromosome 12q24.
Last Evaluated: Dec 12, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:4082342
Stormorken syndrome is an autosomal dominant disorder characterized by mild bleeding tendency due to platelet dysfunction, thrombocytopenia, anemia, asplenia, tubular aggregate myopathy, congenital miosis, and ichthyosis. Additional features may include headache or recurrent stroke-like episodes (summary by Misceo et al., 2014).
Last Evaluated: Dec 12, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:4082342
Likely benign
Hetero
Gene:
TTN
Variant:
c.95068T>C
(p.Cys31690Arg)
rsID: rs56061641
Ref Allele: A
Alt Allele: G
Freq: 0.0167%rare
CADD: 23.7
ClinVar Submissions (7)
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178537118
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178537118
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178537118
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178537118
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178537118
Conflicting/Uncertain
Hetero
Gene:
REPS1
Variant:
c.338C>A
(p.Ala113Glu)
rsID: rs201191394
Ref Allele: G
Alt Allele: T
Freq: 0.0175%rare
CADD: 24.4
ClinVar Submissions (2)
Last Evaluated: Mar 27, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 6:138945637
OMIM Allelic Variant: 614825.0002
Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Ten types and their associated genes are recognized. The age of onset ranges from infancy to late adulthood; the rate of progression varies. Cognitive decline occurs in some subtypes, but more often cognition is relatively spared. Cerebellar atrophy is a frequent finding in some subtypes.
Last Evaluated: Mar 27, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 6:138945637
OMIM Allelic Variant: 614825.0002
Clinically Significant Pathogenic
Hetero
Gene:
DHH
Variant:
c.*159G>T
rsID: rs886049489
Ref Allele: C
Alt Allele: A
Freq: 0.0175%rare
CADD: 5.766
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 12:49089700
Conflicting/Uncertain
Hetero
Gene:
MRE11
Variant:
c.529G>A
(p.Ala177Thr)
rsID: rs142996063
Ref Allele: C
Alt Allele: T
Freq: 0.0183%rare
CADD: 26.7
ClinVar Submissions (7)
Ataxia-telangiectasia-like disorder-1 is an autosomal recessive disorder characterized clinically by progressive cerebellar degeneration resulting in ataxia and oculomotor apraxia. Laboratory studies of patient cells showed increased susceptibility to radiation, consistent with a defect in DNA repair. The disorder shares some phenotypic features of ataxia-telangiectasia (AT; 208900), but telangiectases and immune deficiency are not present in ATLD1 (summary by Hernandez et al., 1993 and Stewart et al., 1999). Genetic Heterogeneity of Ataxia-Telangiectasia-Like Disorder See also ATLD2 (615919), caused by mutation in the PCNA gene (176740) on chromosome 20p12.
Last Evaluated: Aug 01, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:94478750
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Aug 01, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:94478750
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 01, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:94478750
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 01, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:94478750
Conflicting/Uncertain
Hetero
Gene:
NEK8
Variant:
c.582C>T
(p.Tyr194=)
rsID: rs201773965
Ref Allele: C
Alt Allele: T
Freq: 0.0191%rare
CADD: 12.66
ClinVar Submissions (1)
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 17:28735335
Conflicting/Uncertain
Hetero
Gene:
TTN
Variant:
c.25721A>G
(p.Asn8574Ser)
rsID: rs146057575
Ref Allele: T
Alt Allele: C
Freq: 0.0199%rare
CADD: 14.26
ClinVar Submissions (7)
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178713986
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178713986
Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, Udd distal myopathy can remain unnoticed even in the elderly.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178713986
Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support. The disease course varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178713986
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178713986
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178713986
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178713986
Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between age 20 months and four years. In the first decade of life, global motor performances are stable or tend to improve. Moderate joint and neck contractures and spinal rigidity may start in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction starts between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178713986
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178713986
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178713986
Conflicting/Uncertain
Hetero
Gene:
NT5C2
Variant:
c.634-14T>G
rsID: rs200522283
Ref Allele: A
Alt Allele: C
Freq: 0.0207%rare
CADD: 7.297
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:103098998
Likely benign
Hetero
Gene:
SCN9A
Variant:
c.1947G>A
(p.Thr649=)
rsID: rs200014315
Ref Allele: C
Alt Allele: T
Freq: 0.0295%rare
CADD: 1.837
ClinVar Submissions (4)
A syndrome characterized by indifference to PAIN despite the ability to distinguish noxious from non-noxious stimuli. Absent corneal reflexes and INTELLECTUAL DISABILITY may be associated. Familial forms with autosomal recessive and autosomal dominant patterns of inheritance have been described. (Adams et al., Principles of Neurology, 6th ed, p1343)
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
Genetic epilepsy with febrile seizures plus (GEFS+) is a spectrum of seizure disorders of varying severity. GEFS+ is usually diagnosed in families whose members have a combination of febrile seizures, which are triggered by a high fever, and recurrent seizures (epilepsy) of other types, including seizures that are not related to fevers (afebrile seizures). The additional seizure types usually involve both sides of the brain (generalized seizures); however, seizures that involve only one side of the brain (partial seizures) occur in some affected individuals. The most common types of seizure in people with GEFS+ include myoclonic seizures, which cause involuntary muscle twitches; atonic seizures, which involve sudden episodes of weak muscle tone; and absence seizures, which cause loss of consciousness for short periods that appear as staring spells.The most common and mildest feature of the GEFS+ spectrum is simple febrile seizures, which begin in infancy and usually stop by age 5. When the febrile seizures continue after age 5 or other types of seizure develop, the condition is called febrile seizures plus (FS+). Seizures in FS+ usually end in early adolescence.A condition called Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI) is often considered part of the GEFS+ spectrum and is the most severe disorder in this group. Affected infants typically have prolonged seizures lasting several minutes (status epilepticus), which are triggered by fever. Other seizure types, including afebrile seizures, begin in early childhood. These types can include myoclonic or absence seizures. In Dravet syndrome, these seizures are difficult to control with medication, and they can worsen over time. A decline in brain function is also common in Dravet syndrome. Affected individuals usually develop normally in the first year of life, but then development stalls, and some affected children lose already-acquired skills (developmental regression). Many people with Dravet syndrome have difficulty coordinating movements (ataxia) and intellectual disability.Some people with GEFS+ have seizure disorders of intermediate severity that may not fit into the classical diagnosis of simple febrile seizures, FS+, or Dravet syndrome.Family members with GEFS+ may have different combinations of febrile seizures and epilepsy. For example, one affected family member may have only febrile seizures, while another also has myoclonic epilepsy. While GEFS+ is usually diagnosed in families, it can occur in individuals with no history of the condition in their family.
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
Paroxysmal extreme pain disorder, formerly known as familial rectal pain, is characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. Onset is usually in the neonatal period or infancy (Fertleman et al., 2006).
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
SCN1A-related seizure disorders encompass a spectrum that ranges from simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome (also known as severe myoclonic epilepsy in infancy [SMEI] or polymorphic myoclonic epilepsy in infancy [PMEI]) are usually associated with progressive dementia. Less commonly observed phenotypes include myoclonic-astatic epilepsy (MAE or Doose syndrome), Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A-related seizure disorders can vary even within the same family.
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
Small fiber neuropathy is a condition characterized by severe pain attacks that typically begin in the feet or hands. As a person ages, the pain attacks can affect other regions. Some people initially experience a more generalized, whole-body pain. The attacks usually consist of pain described as stabbing or burning, or abnormal skin sensations such as tingling or itchiness. In some individuals, the pain is more severe during times of rest or at night. The signs and symptoms of small fiber neuropathy usually begin in adolescence to mid-adulthood.Individuals with small fiber neuropathy cannot feel pain that is concentrated in a very small area, such as the prick of a pin. However, they have an increased sensitivity to pain in general (hyperalgesia) and experience pain from stimulation that typically does not cause pain (hypoesthesia). People affected with this condition may also have a reduced ability to differentiate between hot and cold. However, in some individuals, the pain attacks are provoked by cold or warm triggers.Some affected individuals have urinary or bowel problems, episodes of rapid heartbeat (palpitations), dry eyes or mouth, or abnormal sweating. They can also experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting.Small fiber neuropathy is considered a form of peripheral neuropathy because it affects the peripheral nervous system, which connects the brain and spinal cord to muscles and to cells that detect sensations such as touch, smell, and pain.
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:166281803
Conflicting/Uncertain
Hetero
Gene:
ITPR1
Variant:
c.3876C>T
(p.His1292=)
rsID: rs61757108
Ref Allele: C
Alt Allele: T
Freq: 0.0366%rare
CADD: 18.95
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 03, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:4691236
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 03, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:4691236
Conflicting/Uncertain
Hetero
Gene:
APOB
Variant:
c.9855C>T
(p.Ile3285=)
rsID: rs72654403
Ref Allele: G
Alt Allele: A
Freq: 0.0406%rare
CADD: 0.303
ClinVar Submissions (4)
Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:21007013
Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:21007013
Hypobetalipoproteinemia (FBHL) and abetalipoproteinemia (ABL; 200100) are rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy, and coagulopathy. Hepatic steatosis is also common. The root cause of both disorders is improper packaging and secretion of apolipoprotein B-containing particles. Obligate heterozygous parents of FBHL patients typically have half normal levels of apoB-containing lipoproteins consistent with autosomal codominant inheritance, whereas obligate heterozygous parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance (summary by Lee and Hegele, 2014). Genetic Heterogeneity of Familial Hypobetalipoproteinemia Familial hypobetalipoproteinemia-2 (FHBL2; 605019) is caused by mutation in the ANGPTL3 gene (604774) on chromosome 1p31.
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:21007013
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:21007013
Benign/Likely benign
Hetero
Gene:
ELN
Variant:
c.*562A>C
rsID: rs539096901
Ref Allele: A
Alt Allele: C
Freq: 0.0486%rare
CADD: 9.67
ClinVar Submissions (1)
Cutis laxa is a disorder of connective tissue, which is the tissue that forms the body's supportive framework. Connective tissue provides structure and strength to the muscles, joints, organs, and skin.The term "cutis laxa" is Latin for loose or lax skin, and this condition is characterized by skin that is sagging and not stretchy (inelastic). The skin often hangs in loose folds, causing the face and other parts of the body to have a droopy appearance. Extremely wrinkled skin may be particularly noticeable on the neck and in the armpits and groin.Cutis laxa can also affect connective tissue in other parts of the body, including the heart, blood vessels, joints, intestines, and lungs. The disorder can cause heart problems and abnormal narrowing, bulging, or tearing of critical arteries. Affected individuals may have soft out-pouchings in the lower abdomen (inguinal hernia) or around the belly button (umbilical hernia). Pouches called diverticula can also develop in the walls of certain organs, such as the bladder and intestines. During childhood, some people with cutis laxa develop a lung disease called emphysema, which can make it difficult to breathe. Depending on which organs and tissues are affected, the signs and symptoms of cutis laxa can range from mild to life-threatening.Researchers have described several different forms of cutis laxa. The forms are often distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive, or X-linked. In general, the autosomal recessive forms of cutis laxa tend to be more severe than the autosomal dominant forms. In addition to the features described above, some people with autosomal recessive cutis laxa have delayed development, intellectual disability, seizures, and problems with movement that can worsen over time.The X-linked form of cutis laxa is often called occipital horn syndrome. This form of the disorder is considered a mild type of Menkes syndrome, which is a condition that affects copper levels in the body. In addition to sagging and inelastic skin, occipital horn syndrome is characterized by wedge-shaped calcium deposits in a bone at the base of the skull (the occipital bone), coarse hair, and loose joints.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:74069262
Supravalvular aortic stenosis (SVAS) is a heart defect that develops before birth. This defect is a narrowing (stenosis) of the large blood vessel that carries blood from the heart to the rest of the body (the aorta). The condition is described as supravalvular because the section of the aorta that is narrowed is located just above the valve that connects the aorta with the heart (the aortic valve). Some people with SVAS also have defects in other blood vessels, most commonly stenosis of the artery from the heart to the lungs (the pulmonary artery). An abnormal heart sound during a heartbeat (heart murmur) can often be heard during a chest exam. If SVAS is not treated, the aortic narrowing can lead to shortness of breath, chest pain, and ultimately heart failure.The severity of SVAS varies considerably, even among family members. Some affected individuals die in infancy, while others never experience symptoms of the disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:74069262
Likely benign
Hetero
Gene:
BMPR2
Variant:
c.*6525G>A
rsID: rs527620155
Ref Allele: G
Alt Allele: A
Freq: 0.0534%rare
CADD: 10.41
ClinVar Submissions (1)
Pulmonary arterial hypertension (PAH) is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries. When a sufficient number of vessels are occluded, the resistance to blood flow through the lungs increases, and the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary blood flow. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure ensues. Initial symptoms include dyspnea (60%), fatigue (19%), syncope (8%), chest pain (7%), palpitations (5%), and leg edema (3%). All ages are affected, but the mean age at diagnosis is 36 years. Mean survival after diagnosis is 2.8 years; current therapy does improve clinical function but has modest effect on survival. The term "heritable PAH" (HPAH) includes familial PAH (PAH that occurs in two or more family members) and simplex PAH (i.e., a single occurrence in a family) when a pathogenic variant has been identified. Most heritable PAH (75%) is caused by a pathogenic variant in BMPR2; pathogenic variants in other genes (i.e., ACVRL1, KCNK3, CAV1, SMAD9, BMPR1B) are considerably less common (1%-3%). HPAH has identical symptoms, signs, and histology as PAH of unknown cause. The time from onset of symptoms to diagnosis may be shorter in individuals with familial PAH, possibly because of familial awareness of the disease. Three retrospective studies suggest that persons with PAH who have a BMPR2 pathogenic variant exhibit more severe disease.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:202566471
Likely benign
Hetero
Gene:
LRP2
Variant:
c.6048C>T
(p.Ala2016=)
rsID: rs144449508
Ref Allele: G
Alt Allele: A
Freq: 0.0557%rare
CADD: 0.081
ClinVar Submissions (1)
Donnai-Barrow syndrome (DBS) is characterized by typical craniofacial features (large anterior fontanel, wide metopic suture, widow's peak, markedly widely spaced eyes, enlarged globes, downslanted palpebral fissures, posteriorly rotated ears, depressed nasal bridge, and short nose. Ocular complications include high myopia, retinal detachment, retinal dystrophy, and progressive vision loss. Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele. Both inter- and intrafamilial phenotypic variability are observed.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:169212200
Conflicting/Uncertain
Hetero
Gene:
CR2
Variant:
c.1676G>A
(p.Gly559Glu)
rsID: rs143614333
Ref Allele: G
Alt Allele: A
Freq: 0.0565%rare
CADD: 23.6
ClinVar Submissions (3)
Common variable immune deficiency (CVID) is a disorder that impairs the immune system. People with CVID are highly susceptible to infection from foreign invaders such as bacteria, or more rarely, viruses and often develop recurrent infections, particularly in the lungs, sinuses, and ears. Pneumonia is common in people with CVID. Over time, recurrent infections can lead to chronic lung disease. Affected individuals may also experience infection or inflammation of the gastrointestinal tract, which can cause diarrhea and weight loss. Abnormal accumulation of immune cells causes enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly) in some people with CVID. Immune cells can accumulate in other organs, forming small lumps called granulomas.Approximately 25 percent of people with CVID have an autoimmune disorder, which occurs when the immune system malfunctions and attacks the body's tissues and organs. The blood cells are most frequently affected by autoimmune attacks in CVID; the most commonly occurring autoimmune disorders are immune thrombocytopenia, which is an abnormal bleeding disorder caused by a decrease in cell fragments involved in blood clotting called platelets, and autoimmune hemolytic anemia, which results in premature destruction of red blood cells. Other autoimmune disorders such as rheumatoid arthritis can occur. Individuals with CVID also have a greater than normal risk of developing certain types of cancer, including a cancer of immune system cells called non-Hodgkin lymphoma and less frequently, stomach (gastric) cancer.People with CVID may start experiencing signs and symptoms of the disorder anytime between childhood and adulthood; most people with CVID are diagnosed in their twenties or thirties. The life expectancy of individuals with CVID varies depending on the severity and frequency of illnesses they experience. Most people with CVID live into adulthood.There are many different types of CVID that are distinguished by genetic cause. People with the same type of CVID may have varying signs and symptoms.
Last Evaluated: Mar 31, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:207472877
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 31, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:207472877
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 31, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:207472877
Conflicting/Uncertain
Hetero
Gene:
RBBP8
Variant:
c.891A>G
(p.Glu297=)
rsID: rs140403315
Ref Allele: A
Alt Allele: G
Freq: 0.0605%rare
CADD: 7.053
ClinVar Submissions (1)
A craniodigital syndrome marked by characteristic facies, microcephaly, retrognathia, symmetrical digital defects, and retarded mental development.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 18:22991020
A rare autosomal recessive inherited syndrome caused by mutations in the ATR gene, RBBP8 gene, CENPJ gene, CEP152 gene, CEP63 gene, NIN gene, DNA2 gene, or TRAIP gene. It is characterized by intrauterine growth retardation, dwarfism, microcephaly, mental retardation, and a "bird-headed" facial appearance.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 18:22991020
Conflicting/Uncertain
Hetero
Gene:
PRKDC
Variant:
c.3709G>A
(p.Ala1237Thr)
rsID: rs191531119
Ref Allele: C
Alt Allele: T
Freq: 0.0621%rare
CADD: 1.757
ClinVar Submissions (2)
Last Evaluated: Jul 19, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 8:47893277
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 19, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 8:47893277
Conflicting/Uncertain
Hetero
Gene:
MAP2K2
Variant:
c.528+46C>T
rsID: rs377101954
Ref Allele: G
Alt Allele: A
Freq: 0.0621%rare
CADD: 2.478
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:4102330
Benign
Hetero
Gene:
EFEMP2
Variant:
c.*282C>T
rsID: rs572394429
Ref Allele: G
Alt Allele: A
Freq: 0.0669%rare
CADD: 0.137
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:65866636
Conflicting/Uncertain
Hetero
Gene:
DNAH5
Variant:
c.11570+124G>C
rsID: rs543104462
Ref Allele: C
Alt Allele: G
Freq: 0.0685%rare
CADD: 0.095
ClinVar Submissions (2)
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have "neonatal respiratory distress" requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Last Evaluated: Aug 22, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:13735694
Likely benign
Hetero
Gene:
RYR1
Variant:
c.10119G>A
(p.Val3373=)
rsID: rs140689610
Ref Allele: G
Alt Allele: A
Freq: 0.0693%rare
CADD: 7.717
ClinVar Submissions (5)
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:38519314
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:38519314
Central core disease (CCD) is characterized by muscle weakness ranging from mild to severe. Most affected individuals have mild disease with symmetric proximal muscle weakness and variable involvement of facial and neck muscles. The extraocular muscles are often spared. Motor development is usually delayed, but in general, most affected individuals acquire independent ambulation. Life span is usually normal. Severe disease is early in onset with profound hypotonia often accompanied by poor fetal movement, spinal deformities, hip dislocation, joint contractures, poor suck, and respiratory insufficiency requiring assisted ventilation. The outcome ranges from death in infancy to survival beyond age five years. The weakness in CCD is not typically progressive.
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:38519314
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:38519314
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:38519314
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:38519314
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:38519314
Conflicting/Uncertain
Hetero
Gene:
TTN
Variant:
c.*265+213933G>A
rsID: rs55938627
Ref Allele: C
Alt Allele: T
Freq: 0.0733%rare
CADD: 8.318
ClinVar Submissions (9)
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, Udd distal myopathy can remain unnoticed even in the elderly.
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support. The disease course varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between age 20 months and four years. In the first decade of life, global motor performances are stable or tend to improve. Moderate joint and neck contractures and spinal rigidity may start in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction starts between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178531387
Conflicting/Uncertain
Hetero
Gene:
SEC63
Variant:
c.340-12_340-7delGTTTTTinsCCC
rsID: rs1554237221
Ref Allele: AAAAAC
Alt Allele: A
Freq: 0.0749%rare
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 14, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:107921916
Benign/Likely benign
Hetero
Gene:
TRIP11
Variant:
c.*290A>G
rsID: rs189206458
Ref Allele: T
Alt Allele: C
Freq: 0.0749%rare
CADD: 0.561
ClinVar Submissions (1)
A rare group of disorders characterized by defective development of bones and cartilage.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 14:91969383
Conflicting/Uncertain
Hetero
Gene:
HNF4A
Variant:
c.492+6G>A
rsID: rs182980547
Ref Allele: G
Alt Allele: A
Freq: 0.0749%rare
CADD: 0.142
ClinVar Submissions (3)
Monogenic diabetes caused by inactivating mutation(s) in the gene HNF4A, encoding hepatocyte nuclear factor 4-alpha.
Last Evaluated: Jul 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 20:44413806
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 20:44413806
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 20:44413806
Conflicting/Uncertain
Hetero
Gene:
DLD
Variant:
c.788G>A
(p.Arg263His)
rsID: rs145670503
Ref Allele: G
Alt Allele: A
Freq: 0.0804%rare
CADD: 33
ClinVar Submissions (3)
The phenotypes of dihydrolipoamide dehydrogenase (DLD) deficiency are an overlapping continuum that ranges from early-onset neurologic manifestations to adult-onset isolated liver involvement. Early-onset DLD deficiency typically manifests as a hypotonic infant with lactic acidosis. Affected infants frequently do not survive their initial metabolic decompensation, or die within the first few years of life during a recurrent metabolic decompensation. Children who live beyond the first two to three years frequently exhibit growth deficiencies and residual neurologic deficits (intellectual disability, spasticity, ataxia, and seizures). In contrast, isolated liver involvement can present as early as the neonatal period and as late as the third decade. Evidence of liver injury/failure is preceded by nausea and emesis and frequently associated with encephalopathy and/or coagulopathy. Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes patients frequently return to baseline with no residual neurologic deficit or intellectual disability. Liver failure can result in death, even in those with late-onset disease.
Last Evaluated: May 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:107915609
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:107915609
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:107915609
Conflicting/Uncertain
Hetero
Gene:
WDR35
Variant:
c.770T>C
(p.Val257Ala)
rsID: rs142955097
Ref Allele: A
Alt Allele: G
Freq: 0.0836%rare
CADD: 22.2
ClinVar Submissions (3)
Cranioectodermal dysplasia (CED), a ciliopathy also known as Sensenbrenner syndrome, is a multisystem disorder with skeletal involvement (narrow thorax, shortened proximal limbs, and brachydactyly), ectodermal features (widely-spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth retardation, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus/epicanthus, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage renal disease (ESRD) in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy, other manifestations of ciliopathies, are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
Last Evaluated: Jun 21, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:19973675
Cranioectodermal dysplasia (CED), a ciliopathy also known as Sensenbrenner syndrome, is a multisystem disorder with skeletal involvement (narrow thorax, shortened proximal limbs, and brachydactyly), ectodermal features (widely-spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth retardation, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus/epicanthus, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage renal disease (ESRD) in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy, other manifestations of ciliopathies, are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
Last Evaluated: Jun 21, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:19973675
A rare congenital lethal syndrome characterized by the presence of extra fingers and toes and short ribs, the latter resulting in inability of the lungs to expand. The newborn dies shortly after birth.
Last Evaluated: Jun 21, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:19973675
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Last Evaluated: Jun 21, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:19973675
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 21, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:19973675
Conflicting/Uncertain
Hetero
Gene:
CNGB3
Variant:
c.912C>T
(p.Val304=)
rsID: rs117806701
Ref Allele: G
Alt Allele: A
Freq: 0.0836%rare
CADD: 0.057
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 10, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:86647879
Likely benign
Hetero
Gene:
CRTAP
Variant:
c.*1124C>A
rsID: rs570473174
Ref Allele: C
Alt Allele: A
Freq: 0.0908%rare
CADD: 0.712
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:33143572
Conflicting/Uncertain
Hetero
Gene:
ERCC5
Variant:
c.1287T>C
(p.Asp429=)
rsID: rs146853061
Ref Allele: T
Alt Allele: C
Freq: 0.094%rare
CADD: 4.048
ClinVar Submissions (1)
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 13:102862436
Conflicting/Uncertain
Hetero
Gene:
DNAH5
Variant:
c.5882+133A>G
rsID: rs530043272
Ref Allele: T
Alt Allele: C
Freq: 0.0964%rare
CADD: 0.09
ClinVar Submissions (1)
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have "neonatal respiratory distress" requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:13839223
Conflicting/Uncertain
Hetero
Gene:
VAPB
Variant:
c.*3725T>C
rsID: rs574293455
Ref Allele: T
Alt Allele: C
Freq: 0.1083%rare
CADD: 6.363
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 20:58447960
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 20:58447960
Likely benign
Hetero
Gene:
CACNA1H
Variant:
c.3669C>T
(p.Ala1223=)
rsID: rs59954346
Ref Allele: C
Alt Allele: T
Freq: 0.1123%rare
CADD: 13.92
ClinVar Submissions (1)
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:1209337
Idiopathic generalized epilepsy is a broad term that encompasses several common seizure phenotypes, classically including childhood absence epilepsy (CAE, ECA; see 600131), juvenile absence epilepsy (JAE, EJA; see 607631), juvenile myoclonic epilepsy (JME, EJM; see 254770), and epilepsy with grand mal seizures on awakening (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). These recurrent seizures occur in the absence of detectable brain lesions and/or metabolic abnormalities. Seizures are initially generalized with a bilateral, synchronous, generalized, symmetrical EEG discharge (Zara et al., 1995; Lu and Wang, 2009). See also childhood absence epilepsy (ECA1; 600131), which has also been mapped to 8q24. Of note, benign neonatal epilepsy 2 (EBN2; 121201) is caused by mutation in the KCNQ3 gene (602232) on 8q24. Genetic Heterogeneity of Idiopathic Generalized Epilepsy EIG1 has been mapped to chromosome 8q24. Other loci or genes associated with EIG include EIG2 (606972) on 14q23; EIG3 (608762) on 9q32; EIG4 (609750) on 10q25; EIG5 (611934) on 10p11; EIG6 (611942), caused by mutation in the CACNA1H gene (607904) on 16p; EIG7 (604827) on 15q14; EIG8 (612899), caused by mutation in the CASR gene (601199) on 3q13.3-q21; EIG9 (607682), caused by mutation in the CACNB4 gene (601949) on 2q22-q23; EIG10 (613060), caused by mutation in the GABRD gene (137163) on 1p36.3; EIG11 (607628), caused by variation in the CLCN2 gene (600570) on 3q36; EIG12 (614847), caused by mutation in the SLC2A1 gene (138140) on 1p34; EIG13 (611136), caused by mutation in the GABRA1 gene (137160) on 5q34; EIG14 (616685), caused by mutation in the SLC12A5 gene (606726) on 20q12; and EIG15 (618357), caused by mutation in the RORB gene (601972) on 9q22.
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:1209337
Benign
Hetero
Gene:
ETFA
Variant:
c.826A>C
(p.Ile276Leu)
rsID: rs141200145
Ref Allele: T
Alt Allele: G
Freq: 0.1179%rare
CADD: 23.3
ClinVar Submissions (2)
Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (GA1; 231670) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be indistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case (Goodman, 1993; Olsen et al., 2003). The heterogeneous clinical features of patients with MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in patients with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress (summary by Frerman and Goodman, 2001). Importantly, riboflavin treatment has been shown to ameliorate the symptoms and metabolic profiles in many MADD patients, particularly those with type III, the late-onset and mildest form (Liang et al., 2009).
Last Evaluated: Jan 17, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:76231389
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 17, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:76231389
Conflicting/Uncertain
Hetero
Gene:
CELSR2
Variant:
c.6859G>A
(p.Val2287Ile)
rsID: rs141489111
Ref Allele: G
Alt Allele: A
Freq: 0.1234%rare
CADD: 20.3
ClinVar Submissions (1)
Last Evaluated: Jan 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:109269470
Conflicting/Uncertain
Hetero
Gene:
ARID1B
Variant:
c.942C>A
(p.Gly314=)
rsID: rs184815562
Ref Allele: C
Alt Allele: A
Freq: 0.129%rare
CADD: 15.59
ClinVar Submissions (2)
Last Evaluated: May 06, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:156778871
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 06, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:156778871
Benign
Hetero
Gene:
BMP2
Variant:
c.552G>A
(p.Ser184=)
rsID: rs142811428
Ref Allele: G
Alt Allele: A
Freq: 0.1457%rare
CADD: 2.593
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 16, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 20:6778450
Likely benign
Hetero
Gene:
ACE
Variant:
c.3801C>T
(p.Ile1267=)
rsID: rs144242912
Ref Allele: C
Alt Allele: T
Freq: 0.1497%rare
CADD: 6.201
ClinVar Submissions (1)
A developmental defect characterized by absence or poor development of proximal renal tubules.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 17:63497246
Conflicting/Uncertain
Hetero
Gene:
CDC73
Variant:
c.*2446C>T
rsID: rs572307472
Ref Allele: C
Alt Allele: T
Freq: 0.1529%rare
CADD: 0.041
ClinVar Submissions (1)
The spectrum of CDC73-related disorders includes the following phenotypes: Hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Primary hyperparathyroidism, the main finding of HPT-JT syndrome, occurs in up to 95% of affected individuals; onset is typically in late adolescence or early adulthood. HPT-JT-associated primary hyperparathyroidism is usually caused by a single parathyroid adenoma. In approximately 10%-15% of individuals, primary hyperparathyroidism is caused by parathyroid carcinoma. Ossifying fibromas of the mandible or maxilla, also known as cementifying fibromas and cemento-ossifying fibromas, occur in 30%-40% of individuals with HPT-JT syndrome. Although benign, these tumors can be locally aggressive and may continue to enlarge if not treated. Approximately 20% of individuals with HPT-JT syndrome have kidney lesions, most commonly cysts; renal hamartomas and (more rarely) Wilms tumor have also been reported. Benign and malignant uterine tumors appear to be common in women with HPT-JT syndrome. Parathyroid carcinoma. Most parathyroid carcinomas are functional, resulting in hyperparathyroidism and a high serum calcium level; however, non-functioning parathyroid carcinomas are also rarely described in individuals with a CDC73-related disorder. A germline CDC73 pathogenic variant has been identified in 20%-29% of individuals with apparently sporadic parathyroid carcinoma. Familial isolated hyperparathyroidism (FIHP). FIHP is characterized by primary hyperparathyroidism without other associated syndromic features. Individuals with CDC73-related FIHP tend to have a more severe clinical presentation and younger age of onset than individuals with FIHP in whom a CDC73 pathogenic variant has not been identified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:193253158
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:193253158
The spectrum of CDC73-related disorders includes the following phenotypes: Hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Primary hyperparathyroidism, the main finding of HPT-JT syndrome, occurs in up to 95% of affected individuals; onset is typically in late adolescence or early adulthood. HPT-JT-associated primary hyperparathyroidism is usually caused by a single parathyroid adenoma. In approximately 10%-15% of individuals, primary hyperparathyroidism is caused by parathyroid carcinoma. Ossifying fibromas of the mandible or maxilla, also known as cementifying fibromas and cemento-ossifying fibromas, occur in 30%-40% of individuals with HPT-JT syndrome. Although benign, these tumors can be locally aggressive and may continue to enlarge if not treated. Approximately 20% of individuals with HPT-JT syndrome have kidney lesions, most commonly cysts; renal hamartomas and (more rarely) Wilms tumor have also been reported. Benign and malignant uterine tumors appear to be common in women with HPT-JT syndrome. Parathyroid carcinoma. Most parathyroid carcinomas are functional, resulting in hyperparathyroidism and a high serum calcium level; however, non-functioning parathyroid carcinomas are also rarely described in individuals with a CDC73-related disorder. A germline CDC73 pathogenic variant has been identified in 20%-29% of individuals with apparently sporadic parathyroid carcinoma. Familial isolated hyperparathyroidism (FIHP). FIHP is characterized by primary hyperparathyroidism without other associated syndromic features. Individuals with CDC73-related FIHP tend to have a more severe clinical presentation and younger age of onset than individuals with FIHP in whom a CDC73 pathogenic variant has not been identified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:193253158
Conflicting/Uncertain
Hetero
Gene:
EYS
Variant:
c.6119T>A
(p.Val2040Asp)
rsID: rs201580493
Ref Allele: A
Alt Allele: T
Freq: 0.1561%rare
CADD: 25.7
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 17, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:64307042
Benign/Likely benign
Hetero
Gene:
SLC25A22
Variant:
c.*328C>T
rsID: rs187161044
Ref Allele: G
Alt Allele: A
Freq: 0.1561%rare
CADD: 1.72
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:791587
Conflicting/Uncertain
Hetero
Gene:
AIRE
Variant:
c.63C>T
(p.Ala21=)
rsID: rs371796437
Ref Allele: C
Alt Allele: T
Freq: 0.1561%rare
CADD: 1.02
ClinVar Submissions (2)
Autoimmune polyglandular syndrome type I is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis (Neufeld et al., 1981).
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:44286069
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:44286069
Benign/Likely benign
Hetero
Gene:
HUWE1
Variant:
c.5091A>G
(p.Gly1697=)
rsID: rs149893977
Ref Allele: T
Alt Allele: C
Freq: 0.1561%rare
ClinVar Submissions (2)
Last Evaluated: Jun 28, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: X:53584256
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 28, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: X:53584256
Conflicting/Uncertain
Hetero
Gene:
BDP1
Variant:
c.4578A>G
(p.Ser1526=)
rsID: rs199669834
Ref Allele: A
Alt Allele: G
Freq: 0.1601%rare
CADD: 3.887
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 30, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:71515051
Likely benign
Hetero
Gene:
MAN1B1
Variant:
c.1173C>T
(p.Ser391=)
rsID: rs145704211
Ref Allele: C
Alt Allele: T
Freq: 0.1609%rare
CADD: 0.375
ClinVar Submissions (2)
Last Evaluated: Jun 27, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:137101591
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 27, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:137101591
Likely benign
Hetero
Gene:
WDR35
Variant:
c.*601A>G
rsID: rs182037850
Ref Allele: T
Alt Allele: C
Freq: 0.1649%rare
CADD: 1.064
ClinVar Submissions (1)
Cranioectodermal dysplasia (CED), a ciliopathy also known as Sensenbrenner syndrome, is a multisystem disorder with skeletal involvement (narrow thorax, shortened proximal limbs, and brachydactyly), ectodermal features (widely-spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth retardation, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus/epicanthus, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage renal disease (ESRD) in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy, other manifestations of ciliopathies, are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:19912957
A rare congenital lethal syndrome characterized by the presence of extra fingers and toes and short ribs, the latter resulting in inability of the lungs to expand. The newborn dies shortly after birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:19912957
Conflicting/Uncertain
Hetero
Gene:
RANGRF
Variant:
c.81C>T
(p.Asp27=)
rsID: rs3809740
Ref Allele: C
Alt Allele: T
Freq: 0.1664%rare
CADD: 18.06
ClinVar Submissions (1)
A disorder in which there is abnormal electrical activity in the heart.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:8288959
Benign
Hetero
Gene:
CLIC2
Variant:
c.478C>G
(p.Pro160Ala)
rsID: rs41304992
Ref Allele: G
Alt Allele: C
Freq: 0.1704%rare
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 30, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: X:155279253
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 30, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: X:155279253
Likely benign
Hetero
Gene:
MECP2
Variant:
c.377+95G>A
rsID: rs267608460
Ref Allele: C
Alt Allele: T
Freq: 0.1712%rare
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 15, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:154032112
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 15, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:154032112
Benign
Hetero
Gene:
ZNF423
Variant:
c.1989G>A
(p.Ala663=)
rsID: rs143468235
Ref Allele: C
Alt Allele: T
Freq: 0.1728%rare
CADD: 3.931
ClinVar Submissions (3)
Last Evaluated: Dec 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:49637163
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:49637163
Benign/Likely benign
Hetero
Gene:
LHCGR
Variant:
c.*535G>A
rsID: rs534109670
Ref Allele: C
Alt Allele: T
Freq: 0.176%rare
CADD: 0.356
ClinVar Submissions (1)
Familial male precocious puberty is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern. Affected males generally exhibit signs of puberty by age 4 years (Shenker et al., 1993).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:48687162
Ovarian or testicular dysfunction associated with high levels of gonadotropins.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:48687162
Leydig cell hypoplasia is an autosomal recessive disorder in which loss of function of the LHCGR gene in the male prevents normal sexual development. Two types of LCH have been defined (Toledo, 1992). Type I, a severe form caused by complete inactivation of LHCGR, is characterized by complete 46,XY male pseudohermaphroditism, low testosterone and high LH levels, total lack of responsiveness to LH/CG challenge, lack of breast development, and absent development of secondary male sex characteristics. Type II, a milder form caused by partial inactivation of the gene, displays a broader range of phenotypic expression ranging from micropenis to severe hypospadias. Females with inactivating mutations in the LHCGR gene display a mild phenotype characterized by defective follicular development and ovulation, amenorrhea, and infertility (review by Themmen and Huhtaniemi, 2000). Reviews Arnhold et al. (2009) noted that the clinical manifestations of female patients with hypogonadotropic hypogonadism due to isolated LH deficiency (HH23; 228300) are very similar to those of women with hypergonadotropic hypogonadism due to inactivating mutations of the LH receptor: all have female external genitalia, spontaneous development of normal pubic hair and breasts at puberty, and normal to late menarche followed by oligoamenorrhea and infertility. Pelvic ultrasound shows a small or normal uterus and normal or enlarged ovaries with cysts. However, women with LHB (152780) mutations can be treated with luteinizing hormone or chorionic gonadotropin (CG; 118860) replacement therapy; women with LH receptor mutations are resistant to LH, and no treatment is effective in recovering their fertility.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:48687162
Likely benign
Hetero
Gene:
FAM161A
Variant:
c.*1129A>C
rsID: rs76144251
Ref Allele: T
Alt Allele: G
Freq: 0.1959%rare
CADD: 6.384
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:61825326
Conflicting/Uncertain
Hetero
Gene:
ADGRV1
Variant:
c.3289G>A
(p.Gly1097Ser)
rsID: rs148097083
Ref Allele: G
Alt Allele: A
Freq: 0.2047%rare
CADD: 34
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 30, 2015
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:90647764
Benign
Hetero
Gene:
FLCN
Variant:
c.1333G>A
(p.Ala445Thr)
rsID: rs41419545
Ref Allele: C
Alt Allele: T
Freq: 0.2126%rare
CADD: 1.994
ClinVar Submissions (11)
Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, stomach, ovary, small bowel, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following lifetime risks for cancer are seen: CRC: 52%-82% (mean age at diagnosis 44-61 years). Endometrial cancer in females: 25%-60% (mean age at diagnosis 48-62 years). Gastric cancer: 6%-13% (mean age at diagnosis 56 years). Ovarian cancer: 4%-12% (mean age at diagnosis 42.5 years; ~30% are diagnosed < age 40 years). The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, trichodiscomas/angiofibromas, perifollicular fibromas, and acrochordons), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear during the third and fourth decades of life and typically increase in size and number with age. Lung cysts are mostly bilateral and multifocal; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Individuals with BHDS are at a sevenfold increased risk for renal tumors that are typically bilateral and multifocal and usually slow growing; median age of tumor diagnosis is 48 years. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (so-called oncocytic hybrid tumor) and chromophobe histologic cell types. Some families have renal tumor and/or autosomal dominant spontaneous pneumothorax without cutaneous manifestations.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
Pneumothorax occurring without traumatic injury to the chest or lung.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:17215284
OMIM Allelic Variant: 607273.0008
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
ALDOA
Variant:
c.1201G>A
(p.Gly401Ser)
rsID: rs138824667
Ref Allele: G
Alt Allele: A
Freq: 0.2158%rare
CADD: 22.2
ClinVar Submissions (2)
Aldolase A deficiency is an autosomal recessive disorder associated with hereditary hemolytic anemia (Kishi et al., 1987).
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:30070156
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 16:30070156
Conflicting/Uncertain
Hetero
Gene:
IHH
Variant:
c.*83A>T
rsID: rs538403599
Ref Allele: T
Alt Allele: A
Freq: 0.2166%rare
CADD: 2.805
ClinVar Submissions (1)
Congenital anomaly of abnormally short fingers or toes.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:219055124
Conflicting/Uncertain
Hetero
Gene:
SYNJ1
Variant:
c.3486A>G
(p.Pro1162=)
rsID: rs368850131
Ref Allele: T
Alt Allele: C
Freq: 0.2206%rare
CADD: 16.4
ClinVar Submissions (2)
Early infantile epileptic encephalopathy-53 is a severe neurodegenerative disorder characterized by onset of intractable seizures in infancy. Affected individuals show hypotonia and very poor or absent global development, resulting in severe intellectual disability and spastic quadriplegia. Some patients may die in childhood (summary by Hardies et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Last Evaluated: Jul 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:32645668
Parkinson disease-20 is an autosomal recessive neurodegenerative disorder characterized by young adult-onset of parkinsonism. Additional features may include seizures, cognitive decline, abnormal eye movements, and dystonia (summary by Krebs et al., 2013 and Quadri et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see PD (168600).
Last Evaluated: Jul 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:32645668
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:32645668
Benign/Likely benign
Hetero
Gene:
MYOT
Variant:
c.981T>C
(p.Asn327=)
rsID: rs148479015
Ref Allele: T
Alt Allele: C
Freq: 0.2238%rare
CADD: 19.8
ClinVar Submissions (5)
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137883548
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137883548
Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%. A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. Peripheral neuropathy is present in about 20% of affected individuals. Overt cardiomyopathy is present in 15%-30%.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137883548
Spheroid body myopathy is a form of myofibrillar myopathy (MFM). Myofibrillar myopathy refers to a genetically heterogeneous group of muscular disorders characterized by a pathologic morphologic pattern of myofibrillar degradation and abnormal accumulation of proteins involved with the sarcomeric Z disc (summary by Foroud et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137883548
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137883548
Likely benign
Hetero
Gene:
MYOT
Variant:
c.*463C>T
rsID: rs149535236
Ref Allele: C
Alt Allele: T
Freq: 0.2262%rare
CADD: 6.092
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137887848
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137887848
Spheroid body myopathy is a form of myofibrillar myopathy (MFM). Myofibrillar myopathy refers to a genetically heterogeneous group of muscular disorders characterized by a pathologic morphologic pattern of myofibrillar degradation and abnormal accumulation of proteins involved with the sarcomeric Z disc (summary by Foroud et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137887848
Likely benign
Hetero
Gene:
NF2
Variant:
c.*1087C>T
rsID: rs148973148
Ref Allele: C
Alt Allele: T
Freq: 0.2278%rare
CADD: 1.015
ClinVar Submissions (1)
Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas. Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings (retinal hamartoma, thickened optic nerves, cortical wedge cataracts, third cranial nerve palsy) may be the first manifestations. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy or hand/foot drop.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 22:29695889
Likely benign
Hetero
Gene:
WT1
Variant:
c.123G>C
(p.Pro41=)
rsID: rs555140661
Ref Allele: C
Alt Allele: G
Freq: 0.231%rare
CADD: 8.661
ClinVar Submissions (5)
Nephrotic syndrome, a malfunction of the glomerular filter, leads to proteinuria, edema, and, in steroid-resistant nephrotic syndrome, end-stage renal disease (ESRD). Renal histopathology in NPHS4 due to WT1 mutations most often shows diffuse mesangial sclerosis (DMS), but can also show focal segmental glomerulosclerosis (FSGS). Both of these terms refer to pathologic findings and may be associated with the same clinical phenotype, namely nephrotic syndrome (review by Schumacher et al., 1998). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).
Last Evaluated: Feb 06, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32435238
Denys-Drash syndrome is a condition that affects the kidneys and genitalia.Denys-Drash syndrome is characterized by kidney disease that begins within the first few months of life. Affected individuals have a condition called diffuse glomerulosclerosis, in which scar tissue forms throughout glomeruli, which are the tiny blood vessels in the kidneys that filter waste from blood. In people with Denys-Drash syndrome, this condition often leads to kidney failure in childhood. People with Denys-Drash syndrome have an estimated 90 percent chance of developing a rare form of kidney cancer known as Wilms tumor. Affected individuals may develop multiple tumors in one or both kidneys.Although males with Denys-Drash syndrome have the typical male chromosome pattern (46,XY), they have gonadal dysgenesis, in which external genitalia do not look clearly male or clearly female (ambiguous genitalia) or the genitalia appear completely female. The testes of affected males are undescended, which means they are abnormally located in the pelvis, abdomen, or groin. As a result, males with Denys-Drash are typically unable to have biological children (infertile).Affected females usually have normal genitalia and have only the kidney features of the condition. Because they do not have all the features of the condition, females are usually given the diagnosis of isolated nephrotic syndrome.
Last Evaluated: Feb 06, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32435238
Frasier syndrome is a rare disorder defined by pseudohermaphroditism and progressive glomerulopathy (Frasier et al., 1964; Haning et al., 1985; Kinberg et al., 1987). Patients present with normal female external genitalia, streak gonads, and XY karyotype, and frequently develop gonadoblastoma (Blanchet et al., 1977). Glomerular symptoms consist of childhood proteinuria and nephrotic syndrome, characterized by nonspecific focal and segmental glomerular sclerosis, progressing to end-stage renal failure in adolescence or early adulthood. Wilms tumor is not a usual feature (Barbaux et al., 1997).
Last Evaluated: Feb 06, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32435238
A multiple malformation syndrome with characteristics of congenital diaphragmatic abnormalities, genital defects and cardiac malformations. Less than 15 patients have been reported worldwide. Ambiguous or female external genitalia are present in individuals with 46,XY karyotype. The genital abnormalities are variable and may include a true double vagina or septate vagina, absent uterus, abnormal male gonads in the presence of normal external female genitalia or male pseudohermaphroditism with abnormal internal female genitalia. Complex cyanotic congenital heart defects, (hypoplastic right lungs, anomalous pulmonary venous return and abnormalities of the diaphragm) are frequent. One patient with rhabdomyomatous dysplasia of the lungs has been reported. Mutations in the WT1 gene have been identified in some patients with Meacham syndrome. All patients reported to date died in early childhood.
Last Evaluated: Feb 06, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32435238
Last Evaluated: Feb 06, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32435238
PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems.
Last Evaluated: Feb 06, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32435238
PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems.
Last Evaluated: Feb 06, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32435238
PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems.
Last Evaluated: Feb 06, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32435238
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 06, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32435238
Benign/Likely benign
Hetero
Gene:
LITAF
Variant:
c.333C>T
(p.Ala111=)
rsID: rs34448402
Ref Allele: G
Alt Allele: A
Freq: 0.2405%rare
CADD: 3.756
ClinVar Submissions (3)
For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:11553577
Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family. Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.Typically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.Affected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.There are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses. These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber. Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs. These abnormalities reduce the strength of the nerve impulse. In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.Sometimes other, historical names are used to refer to particular forms of Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3). Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome.
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:11553577
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:11553577
Benign/Likely benign
Hetero
Gene:
EGF
Variant:
c.2433G>A
(p.Val811=)
rsID: rs149396988
Ref Allele: G
Alt Allele: A
Freq: 0.2453%rare
CADD: 0.032
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 4:109983483
Conflicting/Uncertain
Hetero
Gene:
SLC2A1
Variant:
c.27G>A
(p.Thr9=)
rsID: rs34025424
Ref Allele: C
Alt Allele: T
Freq: 0.2493%rare
CADD: 2.807
ClinVar Submissions (7)
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42943313
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42943313
GLUT1 deficiency syndrome is a disorder affecting the nervous system that can have a variety of neurological signs and symptoms. Approximately 90 percent of affected individuals have a form of the disorder often referred to as common GLUT1 deficiency syndrome. These individuals generally have frequent seizures (epilepsy) beginning in the first months of life. In newborns, the first sign of the disorder may be involuntary eye movements that are rapid and irregular. Babies with common GLUT1 deficiency syndrome have a normal head size at birth, but growth of the brain and skull is often slow, which can result in an abnormally small head size (microcephaly). People with this form of GLUT1 deficiency syndrome may have developmental delay or intellectual disability. Most affected individuals also have other neurological problems, such as stiffness caused by abnormal tensing of the muscles (spasticity), difficulty in coordinating movements (ataxia), and speech difficulties (dysarthria). Some experience episodes of confusion, lack of energy (lethargy), headaches, or muscle twitches (myoclonus), particularly during periods without food (fasting).About 10 percent of individuals with GLUT1 deficiency syndrome have a form of the disorder often known as non-epileptic GLUT1 deficiency syndrome, which is usually less severe than the common form. People with the non-epileptic form do not have seizures, but they may still have developmental delay and intellectual disability. Most have movement problems such as ataxia or involuntary tensing of various muscles (dystonia); the movement problems may be more pronounced than in the common form.Several conditions that were originally given other names have since been recognized to be variants of GLUT1 deficiency syndrome. These include paroxysmal choreoathetosis with spasticity (dystonia 9); paroxysmal exercise-induced dyskinesia and epilepsy (dystonia 18); and certain types of epilepsy. In rare cases, people with variants of GLUT1 deficiency syndrome produce abnormal red blood cells and have uncommon forms of a blood condition known as anemia, which is characterized by a shortage of red blood cells.
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42943313
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42943313
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42943313
Benign/Likely benign
Hetero
Gene:
SCN5A
Variant:
c.6010T>C
(p.Phe2004Leu)
rsID: rs41311117
Ref Allele: A
Alt Allele: G
Freq: 0.2493%rare
CADD: 6.536
ClinVar Submissions (11)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Apr 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:38550362
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Apr 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:38550362
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Apr 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:38550362
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Apr 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:38550362
Last Evaluated: Apr 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:38550362
A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.
Last Evaluated: Apr 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:38550362
Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the ECG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7), hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8), and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.
Last Evaluated: Apr 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:38550362
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:38550362
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 11
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:38550362
Conflicting/Uncertain
Hetero
Gene:
ATP8B1
Variant:
c.208G>A
(p.Asp70Asn)
rsID: rs34719006
Ref Allele: C
Alt Allele: T
Freq: 0.2572%rare
CADD: 23.7
ClinVar Submissions (4)
Intrahepatic cholestasis of pregnancy is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Some women with ICP may also be susceptible to oral contraceptive-induced cholestasis (OCIC) (summary by Pasmant et al., 2012). Genetic Heterogeneity of Intrahepatic Cholestasis of Pregnancy See also ICP3 (614972), caused by mutation in the ABCB4 gene (171060).
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57706561
OMIM Allelic Variant: 602397.0010
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57706561
OMIM Allelic Variant: 602397.0010
ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe to intermediate to mild, based on an individual's clinical findings and laboratory test results, including liver biopsy. Severe ATP8B1 deficiency is characterized by onset of symptoms of cholestasis (pruritus and attacks of jaundice) within the first few months of life. Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months. Without surgical intervention, cirrhosis and evolution to end-stage hepatic failure and death usually ensue before the third decade. Mild ATP8B1 deficiency is characterized by intermittent episodes of cholestasis manifest as severe pruritus and jaundice; chronic liver damage does not typically develop. In contrast to patients in whom bouts of cholestasis are induced only by particular triggers known to increase risk of cholestasis (drug exposure, shifts in hormonal milieu [including those resulting from ingestion of contraceptive drugs or from pregnancy], coexistent malignancy), some or all bouts of cholestasis in individuals with mild ATP8B1 deficiency have different or unknown triggers.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57706561
OMIM Allelic Variant: 602397.0010
ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe to intermediate to mild, based on an individual's clinical findings and laboratory test results, including liver biopsy. Severe ATP8B1 deficiency is characterized by onset of symptoms of cholestasis (pruritus and attacks of jaundice) within the first few months of life. Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months. Without surgical intervention, cirrhosis and evolution to end-stage hepatic failure and death usually ensue before the third decade. Mild ATP8B1 deficiency is characterized by intermittent episodes of cholestasis manifest as severe pruritus and jaundice; chronic liver damage does not typically develop. In contrast to patients in whom bouts of cholestasis are induced only by particular triggers known to increase risk of cholestasis (drug exposure, shifts in hormonal milieu [including those resulting from ingestion of contraceptive drugs or from pregnancy], coexistent malignancy), some or all bouts of cholestasis in individuals with mild ATP8B1 deficiency have different or unknown triggers.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57706561
OMIM Allelic Variant: 602397.0010
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57706561
OMIM Allelic Variant: 602397.0010
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
LRRK2
Variant:
c.5510-9A>G
rsID: rs41286460
Ref Allele: A
Alt Allele: G
Freq: 0.2652%rare
CADD: 0.588
ClinVar Submissions (2)
Last Evaluated: Dec 02, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:40323151
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 02, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:40323151
Benign/Likely benign
Hetero
Gene:
ZFYVE26
Variant:
c.7371+18C>T
rsID: rs149769693
Ref Allele: G
Alt Allele: A
Freq: 0.2716%rare
CADD: 4.787
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:67752326
Likely benign
Hetero
Gene:
TCIRG1
Variant:
c.1249G>A
(p.Ala417Thr)
rsID: rs140963213
Ref Allele: G
Alt Allele: A
Freq: 0.2724%rare
CADD: 26
ClinVar Submissions (2)
Osteopetrosis (OPT) is a life-threatening disease caused by subnormal osteoclast function, with an incidence of 1 in 250,000 births. The disease usually manifests in the first few months of life with macrocephaly and frontal bossing, resulting in a characteristic facial appearance. Defective bone remodeling of the skull results in choanal stenosis with concomitant respiratory problems and feeding difficulties, which are the first clinical manifestation of disease. The expanding bone encroaches on neural foramina, leading to blindness, deafness, and facial palsy. Complete visual loss invariably occurs in all untreated patients, and hearing loss is estimated to affect 78% of patients with OPT. Tooth eruption defects and severe dental caries are common. Calcium feedback hemostasis is impaired, and children with OPT are at risk of developing hypocalcemia with attendant tetanic seizures and secondary hyperparathyroidism. The most severe complication of OPT, limiting survival, is bone marrow insufficiency. The abnormal expansion of cortical and trabecular bone physically limits the availability of medullary space for hematopoietic activity, leading to life-threatening cytopenia and secondary expansion of extramedullary hematopoiesis at sites such as the liver and spleen (summary by Aker et al., 2012). Genetic Heterogeneity of Autosomal Recessive Osteopetrosis Other forms of autosomal recessive infantile malignant osteopetrosis include OPTB4 (611490), which is caused by mutation in the CLCN7 gene (602727) on chromosome 16p13, and OPTB5 (259720), which is caused by mutation in the OSTM1 gene (607649) on chromosome 6q21. A milder, osteoclast-poor form of autosomal recessive osteopetrosis (OPTB2; 259710) is caused by mutation in the TNFSF11 gene (602642) on chromosome 13q14, an intermediate form (OPTB6; 611497) is caused by mutation in the PLEKHM1 gene (611466) on chromosome 17q21, and a severe osteoclast-poor form associated with hypogammaglobulinemia (OPTB7; 612301) is caused by mutation in the TNFRSF11A gene (603499) on chromosome 18q22. Another form of autosomal recessive osteopetrosis (OPTB8; 615085) is caused by mutation in the SNX10 gene (614780) on chromosome 7p15. A form of autosomal recessive osteopetrosis associated with renal tubular acidosis (OPTB3; 259730) is caused by mutation in the CA2 gene (611492) on chromosome 8q21. Autosomal dominant forms of osteopetrosis are more benign (see OPTA1, 607634).
Last Evaluated: Jan 21, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:68047516
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 21, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:68047516
Conflicting/Uncertain
Hetero
Gene:
KLHL3
Variant:
c.*4065C>T
rsID: rs142781557
Ref Allele: G
Alt Allele: A
Freq: 0.2755%rare
CADD: 0.609
ClinVar Submissions (1)
Autosomal dominant pseudohypoaldosteronism type I is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by Geller et al., 1998). Autosomal recessive pseudohypoaldosteronism type I (PHA1B; 264350), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137618033
Likely benign
Hetero
Gene:
KLHL3
Variant:
c.*3128C>G
rsID: rs147801381
Ref Allele: G
Alt Allele: C
Freq: 0.2755%rare
CADD: 4.705
ClinVar Submissions (1)
Autosomal dominant pseudohypoaldosteronism type I is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by Geller et al., 1998). Autosomal recessive pseudohypoaldosteronism type I (PHA1B; 264350), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137618970
Likely benign
Hetero
Gene:
GLDC
Variant:
c.*115A>T
rsID: rs148273307
Ref Allele: T
Alt Allele: A
Freq: 0.2755%rare
CADD: 8.039
ClinVar Submissions (1)
Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inborn error of glycine metabolism defined by deficient activity of the glycine cleavage enzyme and, as a consequence, accumulation of large quantities of glycine in all body tissues including the brain. The majority of glycine encephalopathy presents in the neonatal period (85% as the neonatal severe form and 15% as the neonatal attenuated form). Of those presenting in infancy, 50% have the infantile attenuated form and 50% have the infantile severe form. Overall, 20% of all children presenting as either neonates or infants have a less severe outcome, defined as developmental quotient greater than 20. A minority of patients have mild or atypical forms of glycine encephalopathy. The neonatal form manifests in the first hours to days of life with progressive lethargy, hypotonia, and myoclonic jerks leading to apnea and often death. Surviving infants have profound intellectual disability and intractable seizures. The infantile form is characterized by hypotonia, developmental delay, and seizures. The atypical forms range from milder disease, with onset from late infancy to adulthood, to rapidly progressing and severe disease with late onset.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:6532902
Conflicting/Uncertain
Hetero
Gene:
MPL
Variant:
c.*1180G>A
rsID: rs117166528
Ref Allele: G
Alt Allele: A
Freq: 0.2843%rare
CADD: 2.41
ClinVar Submissions (1)
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder expressed in infancy and characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies (Muraoka et al., 1997). King et al. (2005) proposed a new classification of CAMT based on the course and outcome of the disease, as exemplified by 20 patients: CAMT type I (11 patients) was characterized by early onset of severe pancytopenia, decreased bone marrow activity, and very low platelet counts. CAMT type II (9 patients) was somewhat milder and characterized by transient increases of platelet counts up to nearly normal values during the first year of life and an onset of bone marrow failure at age 3 or later.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:43353952
Thrombocythemia, or thrombocytosis, is a myeloproliferative disorder characterized by excessive platelet production resulting in increased numbers of circulating platelets. Thrombocythemia can be associated with thrombotic or hemorrhagic episodes and occasional leukemic transformation (summary by Wiestner et al., 1998). Genetic Heterogeneity of Thrombocythemia THCYT2 (601977) is caused by germline or somatic mutation in the THPO receptor gene (MPL; 159530) on chromosome 1p34; THCYT3 (614521) is caused by germline or somatic mutation in the JAK2 gene (147796) on chromosome 9p; and a possible X-linked form (THCYTX; 300331) has been reported. Somatic mutations in the TET2 (612839), ASXL1 (612990), SH2B3 (605093), and SF3B1 (605590) genes have also been found in cases of essential thrombocythemia. Somatic mutation in the CALR gene (109091) occurs in approximately 70% of essential thrombocythemia patients who lack JAK2 and MPL mutations (Klampfl et al., 2013; Nangalia et al., 2013).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:43353952
Likely benign
Hetero
Gene:
MPL
Variant:
c.*1603A>C
rsID: rs142139493
Ref Allele: A
Alt Allele: C
Freq: 0.2851%rare
CADD: 0.338
ClinVar Submissions (1)
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder expressed in infancy and characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies (Muraoka et al., 1997). King et al. (2005) proposed a new classification of CAMT based on the course and outcome of the disease, as exemplified by 20 patients: CAMT type I (11 patients) was characterized by early onset of severe pancytopenia, decreased bone marrow activity, and very low platelet counts. CAMT type II (9 patients) was somewhat milder and characterized by transient increases of platelet counts up to nearly normal values during the first year of life and an onset of bone marrow failure at age 3 or later.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:43354375
Thrombocythemia, or thrombocytosis, is a myeloproliferative disorder characterized by excessive platelet production resulting in increased numbers of circulating platelets. Thrombocythemia can be associated with thrombotic or hemorrhagic episodes and occasional leukemic transformation (summary by Wiestner et al., 1998). Genetic Heterogeneity of Thrombocythemia THCYT2 (601977) is caused by germline or somatic mutation in the THPO receptor gene (MPL; 159530) on chromosome 1p34; THCYT3 (614521) is caused by germline or somatic mutation in the JAK2 gene (147796) on chromosome 9p; and a possible X-linked form (THCYTX; 300331) has been reported. Somatic mutations in the TET2 (612839), ASXL1 (612990), SH2B3 (605093), and SF3B1 (605590) genes have also been found in cases of essential thrombocythemia. Somatic mutation in the CALR gene (109091) occurs in approximately 70% of essential thrombocythemia patients who lack JAK2 and MPL mutations (Klampfl et al., 2013; Nangalia et al., 2013).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:43354375
Likely benign
Hetero
Gene:
DTNA
Variant:
c.*29G>A
rsID: rs187308097
Ref Allele: G
Alt Allele: A
Freq: 0.2883%rare
CADD: 17.08
ClinVar Submissions (1)
An uncommon congenital abnormality where the left ventricular myocardium fails to compact during embryonic development, leading to cardiomyopathy with a variable degree of ventricular dysfunction. There is genetic heterogeneity and phenotypic variability. Characteristically, there are typically deep trabeculations in the noncompacted area, with varying proportions of the LV myocardium compacted. LV noncompaction is associated with rhythm abnormalities including Wolff-Parkinson-White syndrome, conduction defects, and ventricular tachyarrhythmias.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:34866190
Likely benign
Hetero
Gene:
USH1C
Variant:
c.381G>T
(p.Gly127=)
rsID: rs41282942
Ref Allele: C
Alt Allele: A
Freq: 0.2947%rare
CADD: 8.62
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:17531160
Benign/Likely benign
Hetero
Gene:
MOCS1
Variant:
c.*2192C>G
rsID: rs151159237
Ref Allele: G
Alt Allele: C
Freq: 0.2986%rare
CADD: 3.039
ClinVar Submissions (1)
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor Deficiency See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:39904933
Conflicting/Uncertain
Hetero
Gene:
KLHL3
Variant:
c.*1106G>T
rsID: rs141393967
Ref Allele: C
Alt Allele: A
Freq: 0.3034%rare
CADD: 0.241
ClinVar Submissions (1)
Autosomal dominant pseudohypoaldosteronism type I is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by Geller et al., 1998). Autosomal recessive pseudohypoaldosteronism type I (PHA1B; 264350), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:137620992
Likely benign
Hetero
Gene:
COQ8B
Variant:
c.1305C>T
(p.Ser435=)
rsID: rs139130454
Ref Allele: G
Alt Allele: A
Freq: 0.3074%rare
CADD: 0.432
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 22, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:40692365
Benign
Hetero
Gene:
KLHL3
Variant:
c.*1657G>A
rsID: rs375193765
Ref Allele: C
Alt Allele: T
Freq: 0.3106%rare
CADD: 0.582
ClinVar Submissions (1)
Autosomal dominant pseudohypoaldosteronism type I is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by Geller et al., 1998). Autosomal recessive pseudohypoaldosteronism type I (PHA1B; 264350), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:137620441
Conflicting/Uncertain
Hetero
Gene:
KIF7
Variant:
c.2501A>G
(p.Gln834Arg)
rsID: rs138354681
Ref Allele: T
Alt Allele: C
Freq: 0.3122%rare
CADD: 28.9
ClinVar Submissions (5)
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Last Evaluated: Mar 07, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:89633777
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 07, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:89633777
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 07, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:89633777
Benign/Likely benign
Hetero
Gene:
WAS
Variant:
c.1378C>T
(p.Pro460Ser)
rsID: rs143885622
Ref Allele: C
Alt Allele: T
Freq: 0.3297%rare
ClinVar Submissions (4)
The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities.
Last Evaluated: Oct 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: X:48689359
The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities.
Last Evaluated: Oct 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: X:48689359
The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities.
Last Evaluated: Oct 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: X:48689359
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: X:48689359
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: X:48689359
Benign/Likely benign
Hetero
Gene:
HSPB1
Variant:
c.9G>A
(p.Glu3=)
rsID: rs77586767
Ref Allele: G
Alt Allele: A
Freq: 0.3377%rare
CADD: 16.69
ClinVar Submissions (4)
Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family. Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.Typically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.Affected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.There are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses. These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber. Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs. These abnormalities reduce the strength of the nerve impulse. In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.Sometimes other, historical names are used to refer to particular forms of Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3). Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome.
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:76302721
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:76302721
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:76302721
Benign/Likely benign
Hetero
Gene:
LAMC3
Variant:
c.3250G>C
(p.Glu1084Gln)
rsID: rs146221263
Ref Allele: G
Alt Allele: C
Freq: 0.3409%rare
CADD: 10.12
ClinVar Submissions (5)
Occipital cortical malformations (OCCM) is an autosomal recessive condition in which affected individuals develop seizures, sometimes associated with transient visual changes. Brain MRI shows both pachygyria and polymicrogyria restricted to the lateral occipital lobes (summary by Barak et al., 2011).
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:131072668
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:131072668
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:131072668
Conflicting/Uncertain
Hetero
Gene:
LAMC3
Variant:
c.3379G>A
(p.Glu1127Lys)
rsID: rs140955110
Ref Allele: G
Alt Allele: A
Freq: 0.3416%rare
CADD: 20.8
ClinVar Submissions (5)
Occipital cortical malformations (OCCM) is an autosomal recessive condition in which affected individuals develop seizures, sometimes associated with transient visual changes. Brain MRI shows both pachygyria and polymicrogyria restricted to the lateral occipital lobes (summary by Barak et al., 2011).
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:131072797
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:131072797
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:131072797
Conflicting/Uncertain
Hetero
Gene:
ST3GAL5
Variant:
c.*415T>C
rsID: rs112372963
Ref Allele: A
Alt Allele: G
Freq: 0.3424%rare
CADD: 6.699
ClinVar Submissions (1)
Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterized by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss (summary by Fragaki et al., 2013). Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood (summary by Boccuto et al., 2014). Not all patients have overt seizures (Lee et al., 2016).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:85839729
Conflicting/Uncertain
Hetero
Gene:
AMACR
Variant:
c.-70G>A
rsID: rs563347179
Ref Allele: C
Alt Allele: T
Freq: 0.3424%rare
CADD: 6.666
ClinVar Submissions (1)
AMACR deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. Serum pristanic acid and C27 bile acid intermediates are increased (summary by Smith et al., 2010).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:34008089
Conflicting/Uncertain
Hetero
Gene:
SLC2A9
Variant:
c.1545C>T
(p.Ser515=)
rsID: rs144428359
Ref Allele: G
Alt Allele: A
Freq: 0.344%rare
CADD: 6.345
ClinVar Submissions (1)
Renal hypouricemia is characterized by impaired uric acid reabsorption at the apical membrane of proximal renal tubule cells. The syndrome is not lethal and may be asymptomatic. However, it is accompanied by nephrolithiasis and exercise-induced acute renal failure in about 10% of patients (Ichida et al., 2008). Genetic Heterogeneity of Renal Hypouricemia See also RHUC2 (612076), which is caused by mutation in the SLC2A9 gene (606142).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:9826475
Likely benign
Hetero
Gene:
LAMC3
Variant:
c.2891-8C>T
rsID: rs199535979
Ref Allele: C
Alt Allele: T
Freq: 0.3448%rare
CADD: 1.843
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:131069664
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:131069664
Conflicting/Uncertain
Hetero
Gene:
MOCOS
Variant:
c.309G>A
(p.Ala103=)
rsID: rs149639104
Ref Allele: G
Alt Allele: A
Freq: 0.3488%rare
CADD: 3.658
ClinVar Submissions (1)
Xanthinuria type II is an autosomal recessive inborn error of metabolism resulting from a defect in the synthesis of the molybdenum cofactor, which is necessary for the 2 enzymes that degrade xanthine: XDH (607633) and AOX1 (602841). Most individuals with type II xanthinuria are asymptomatic, but some develop urinary tract calculi, acute renal failure, or myositis due to tissue deposition of xanthine. Laboratory studies show increased serum and urinary hypoxanthine and xanthine and decreased serum and urinary uric acid (summary by Ichida et al., 2001). Two clinically similar but distinct forms of xanthinuria are recognized. In type I xanthinuria (XAN1; 278300), there is an isolated deficiency of xanthine dehydrogenase resulting from mutation in the XDH gene; in type II, there is a dual deficiency of xanthine dehydrogenase and aldehyde oxidase. Type I patients can metabolize allopurinol, whereas type II patients cannot (Simmonds et al., 1995).
Last Evaluated: Dec 04, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:36199692
Benign
Hetero
Gene:
CACNA1C
Variant:
c.*5147A>G
rsID: rs188226168
Ref Allele: A
Alt Allele: G
Freq: 0.3584%rare
CADD: 4.174
ClinVar Submissions (1)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2696346
Timothy syndrome is a multisystem disorder characterized by cardiac, hand/foot, facial, and neurodevelopmental features. Typical cardiac findings include a rate-corrected QT interval >480 ms, functional 2:1 AV block with bradycardia, tachyarrhythmias, and congenital heart defects (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy). The diagnosis of Timothy syndrome is generally made within the first few days of life although it may be suspected prenatally due to 2:1 AV block or bradycardia in the fetus. Hand/foot findings are unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three. Facial findings include depressed nasal bridge, low-set ears, thin vermilion border of the upper lip, and round face. Neuropsychiatric involvement includes global developmental delays and autism spectrum disorders. Ventricular tachyarrhythmia is the leading cause of death, followed by infection and complications of intractable hypoglycemia. Average age of death is 2.5 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2696346
Likely benign
Hetero
Gene:
ATP8B1
Variant:
c.-48C>T
rsID: rs150844949
Ref Allele: G
Alt Allele: A
Freq: 0.3592%rare
CADD: 22.4
ClinVar Submissions (2)
Progressive familial intrahepatic cholestasis (PFIC) is a disorder that causes progressive liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals.Signs and symptoms of PFIC typically begin in infancy and are related to bile buildup and liver disease. Specifically, affected individuals experience severe itching, yellowing of the skin and whites of the eyes (jaundice), failure to gain weight and grow at the expected rate (failure to thrive), high blood pressure in the vein that supplies blood to the liver (portal hypertension), and an enlarged liver and spleen (hepatosplenomegaly).There are three known types of PFIC: PFIC1, PFIC2, and PFIC3. The types are also sometimes described as shortages of particular proteins needed for normal liver function. Each type has a different genetic cause.In addition to signs and symptoms related to liver disease, people with PFIC1 may have short stature, deafness, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. Affected individuals typically develop liver failure before adulthood.The signs and symptoms of PFIC2 are typically related to liver disease only; however, these signs and symptoms tend to be more severe than those experienced by people with PFIC1. People with PFIC2 often develop liver failure within the first few years of life. Additionally, affected individuals are at increased risk of developing a type of liver cancer called hepatocellular carcinoma.Most people with PFIC3 have signs and symptoms related to liver disease only. Signs and symptoms of PFIC3 usually do not appear until later in infancy or early childhood; rarely, people are diagnosed in early adulthood. Liver failure can occur in childhood or adulthood in people with PFIC3.
Last Evaluated: Feb 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57803023
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 21, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57803023
Conflicting/Uncertain
Hetero
Gene:
FBXW4
Variant:
c.945T>C
(p.Tyr315=)
rsID: rs35614606
Ref Allele: A
Alt Allele: G
Freq: 0.3616%rare
CADD: 15.55
ClinVar Submissions (2)
A rare genetic disorder often inherited in an autosomal manner characterized by limb malformations including syndactyly, median clefts of the hands and/or feet, and partial or complete absence of fingers or toes. It may be associated with other skeletal and extraskeletal abnormalities.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:101612369
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:101612369
Benign/Likely benign
Hetero
Gene:
EYA4
Variant:
c.*2968T>A
rsID: rs181492427
Ref Allele: T
Alt Allele: A
Freq: 0.3639%rare
CADD: 4.882
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:133531773
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:133531773
Conflicting/Uncertain
Hetero
Gene:
ANKH
Variant:
c.*6163A>G
rsID: rs182300014
Ref Allele: T
Alt Allele: C
Freq: 0.3687%rare
CADD: 13.75
ClinVar Submissions (1)
Presence of CALCIUM PYROPHOSPHATE in the connective tissues such as the cartilaginous structures of joints. When accompanied by GOUT-like symptoms, it is referred to as pseudogout.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:14705034
Craniometadiaphyseal dysplasia (CRMDD) is characterized clinically by macrocephaly with frontal prominence, dental hypoplasia, and increased bone fragility. Diagnostic radiologic features include thin bones in the superior part of calvaria with prominent wormian bones, diaphyseal widening of the long tubular bones in early childhood with wide undermineralized metaphyses in older individuals, widened ribs and clavicles, and broadening of short tubular bones with increased transparency and thin cortices (summary by Dhar et al., 2010).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:14705034
Likely benign
Hetero
Gene:
SLC25A20
Variant:
c.*359C>T
rsID: rs116681393
Ref Allele: G
Alt Allele: A
Freq: 0.3759%rare
CADD: 8.621
ClinVar Submissions (1)
Carnitine-acylcarnitine translocase deficiency is a rare autosomal recessive metabolic disorder of long-chain fatty acid oxidation. Metabolic consequences include hypoketotic hypoglycemia under fasting conditions, hyperammonemia, elevated creatine kinase and transaminases, dicarboxylic aciduria, very low free carnitine and abnormal acylcarnitine profile with marked elevation of the long-chain acylcarnitines. Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate. However, presentations at a later age with a milder phenotype have been reported (summary by Rubio-Gozalbo et al., 2004).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:48857351
Conflicting/Uncertain
Hetero
Gene:
LAMC3
Variant:
c.4092C>T
(p.Ser1364=)
rsID: rs141724499
Ref Allele: C
Alt Allele: T
Freq: 0.3791%rare
CADD: 0.992
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:131085585
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 16, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:131085585
Conflicting/Uncertain
Hetero
Gene:
TRAP1
Variant:
c.757A>G
(p.Ile253Val)
rsID: rs113476582
Ref Allele: T
Alt Allele: C
Freq: 0.3831%rare
CADD: 21.8
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 25, 2016
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:3676093
Likely benign
Hetero
Gene:
CTNNA1
Variant:
c.1389+4889T>A
rsID: rs77683255
Ref Allele: T
Alt Allele: A
Freq: 0.3934%rare
CADD: 7.457
ClinVar Submissions (1)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Dec 01, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:138909330
Likely benign
Hetero
Gene:
OTOF
Variant:
c.2215-19C>G
rsID: rs111033427
Ref Allele: G
Alt Allele: C
Freq: 0.403%rare
CADD: 1.234
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:26477768
Benign/Likely benign
Hetero
Gene:
WT1
Variant:
c.1114-9T>C
rsID: rs5030274
Ref Allele: A
Alt Allele: G
Freq: 0.4444%rare
CADD: 13.11
ClinVar Submissions (4)
Nephrotic syndrome, a malfunction of the glomerular filter, leads to proteinuria, edema, and, in steroid-resistant nephrotic syndrome, end-stage renal disease (ESRD). Renal histopathology in NPHS4 due to WT1 mutations most often shows diffuse mesangial sclerosis (DMS), but can also show focal segmental glomerulosclerosis (FSGS). Both of these terms refer to pathologic findings and may be associated with the same clinical phenotype, namely nephrotic syndrome (review by Schumacher et al., 1998). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32396416
Denys-Drash syndrome is a condition that affects the kidneys and genitalia.Denys-Drash syndrome is characterized by kidney disease that begins within the first few months of life. Affected individuals have a condition called diffuse glomerulosclerosis, in which scar tissue forms throughout glomeruli, which are the tiny blood vessels in the kidneys that filter waste from blood. In people with Denys-Drash syndrome, this condition often leads to kidney failure in childhood. People with Denys-Drash syndrome have an estimated 90 percent chance of developing a rare form of kidney cancer known as Wilms tumor. Affected individuals may develop multiple tumors in one or both kidneys.Although males with Denys-Drash syndrome have the typical male chromosome pattern (46,XY), they have gonadal dysgenesis, in which external genitalia do not look clearly male or clearly female (ambiguous genitalia) or the genitalia appear completely female. The testes of affected males are undescended, which means they are abnormally located in the pelvis, abdomen, or groin. As a result, males with Denys-Drash are typically unable to have biological children (infertile).Affected females usually have normal genitalia and have only the kidney features of the condition. Because they do not have all the features of the condition, females are usually given the diagnosis of isolated nephrotic syndrome.
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32396416
Frasier syndrome is a rare disorder defined by pseudohermaphroditism and progressive glomerulopathy (Frasier et al., 1964; Haning et al., 1985; Kinberg et al., 1987). Patients present with normal female external genitalia, streak gonads, and XY karyotype, and frequently develop gonadoblastoma (Blanchet et al., 1977). Glomerular symptoms consist of childhood proteinuria and nephrotic syndrome, characterized by nonspecific focal and segmental glomerular sclerosis, progressing to end-stage renal failure in adolescence or early adulthood. Wilms tumor is not a usual feature (Barbaux et al., 1997).
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32396416
A multiple malformation syndrome with characteristics of congenital diaphragmatic abnormalities, genital defects and cardiac malformations. Less than 15 patients have been reported worldwide. Ambiguous or female external genitalia are present in individuals with 46,XY karyotype. The genital abnormalities are variable and may include a true double vagina or septate vagina, absent uterus, abnormal male gonads in the presence of normal external female genitalia or male pseudohermaphroditism with abnormal internal female genitalia. Complex cyanotic congenital heart defects, (hypoplastic right lungs, anomalous pulmonary venous return and abnormalities of the diaphragm) are frequent. One patient with rhabdomyomatous dysplasia of the lungs has been reported. Mutations in the WT1 gene have been identified in some patients with Meacham syndrome. All patients reported to date died in early childhood.
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32396416
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32396416
PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems.
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32396416
PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems.
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32396416
PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems.
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32396416
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32396416
Benign/Likely benign
Hetero
Gene:
PEX14
Variant:
c.795A>G
(p.Ser265=)
rsID: rs41274484
Ref Allele: A
Alt Allele: G
Freq: 0.4539%rare
CADD: 1.4
ClinVar Submissions (2)
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term ZSD is now used to refer to all individuals with a PEX gene defect regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and other long bones), and liver disease which can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss); neurologic involvement (ataxia, polyneuropathy, and leukodystrophy); liver dysfunction; adrenal insufficiency; and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:10629648
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:10629648
Conflicting/Uncertain
Hetero
Gene:
USH2A
Variant:
c.13440G>A
(p.Arg4480=)
rsID: rs111033378
Ref Allele: C
Alt Allele: T
Freq: 0.4595%rare
CADD: 2.36
ClinVar Submissions (4)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:215674471
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 11, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:215674471
Conflicting/Uncertain
Hetero
Gene:
ZNF335
Variant:
c.826G>A
(p.Ala276Thr)
rsID: rs117802609
Ref Allele: C
Alt Allele: T
Freq: 0.4683%rare
CADD: 1.572
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 10, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 20:45967623
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 10, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 20:45967623
Likely benign
Hetero
Gene:
ADCY1
Variant:
c.897C>T
(p.His299=)
rsID: rs78087585
Ref Allele: C
Alt Allele: T
Freq: 0.4699%rare
CADD: 5.523
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 23, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:45610486
Benign
Hetero
Gene:
ROBO3
Variant:
c.850G>A
(p.Asp284Asn)
rsID: rs142090631
Ref Allele: G
Alt Allele: A
Freq: 0.4699%rare
CADD: 30
ClinVar Submissions (1)
HGPPS is an autosomal recessive neurologic disorder characterized by eye movement abnormalities apparent from birth and childhood-onset progressive scoliosis. These features are associated with a developmental malformation of the brainstem including hypoplasia of the pons and cerebellar peduncles and defective decussation of certain neuronal systems. Cognitive function is normal (summary by Bosley et al., 2005). Genetic Heterogeneity of Familial Horizontal Gaze Palsy With Progressive Scoliosis See also HGPPS2 (617542), caused by mutation in the DCC gene (120470) on chromosome 18q21.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:124870248
Conflicting/Uncertain
Hetero
Gene:
ATR
Variant:
c.3945+483G>A
rsID: rs149815404
Ref Allele: C
Alt Allele: T
Freq: 0.4826%rare
CADD: 11.6
ClinVar Submissions (1)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Dec 01, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:142534597
Likely benign
Hetero
Gene:
COL2A1
Variant:
c.4104C>T
(p.Pro1368=)
rsID: rs12721379
Ref Allele: G
Alt Allele: A
Freq: 0.4938%rare
CADD: 8.876
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 06, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:47974302
Benign/Likely benign
Hetero
Gene:
IGF1R
Variant:
c.*4599C>T
rsID: rs144947320
Ref Allele: C
Alt Allele: T
Freq: 0.4961%rare
CADD: 5.472
ClinVar Submissions (1)
Patients with mutations in the receptor for insulin-like growth factor I show intrauterine growth retardation and postnatal growth failure, resulting in short stature and microcephaly. Other features may include delayed bone age, developmental delay, and dysmorphic features.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:98962041
Conflicting/Uncertain
Hetero
Gene:
KIAA0586
Variant:
c.581T>C
(p.Met194Thr)
rsID: rs61735931
Ref Allele: T
Alt Allele: C
Freq: 0.5041%rare
CADD: 18.37
ClinVar Submissions (2)
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:58442717
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia with or without polydactyly, see SRTD1 (208500).
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:58442717
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:58442717
Benign/Likely benign
Hetero
Gene:
TK2
Variant:
c.231+10C>T
rsID: rs187517309
Ref Allele: G
Alt Allele: A
Freq: 0.5049%rare
CADD: 2.323
ClinVar Submissions (4)
TK2-related mitochondrial DNA (mtDNA) maintenance defect is a phenotypic continuum that ranges from severe to mild. To date, approximately 107 individuals with a molecularly confirmed diagnosis have been reported. Three main subtypes of presentation have been described: Infantile-onset myopathy with neurologic involvement and rapid progression to early death. Affected individuals experience progressive muscle weakness leading to respiratory failure. Some individuals develop dysarthria, dysphagia, and/or hearing loss. Cognitive function is typically spared. Juvenile/childhood onset with generalized proximal weakness and survival to at least 13 years. Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions. Some affected individuals develop respiratory insufficiency, chronic progressive external ophthalmoplegia, dysphagia, and dysarthria.
Last Evaluated: Jul 08, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:66541869
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 08, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:66541869
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 08, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:66541869
Benign/Likely benign
Hetero
Gene:
SLC2A1
Variant:
c.417C>T
(p.Phe139=)
rsID: rs144538918
Ref Allele: G
Alt Allele: A
Freq: 0.5105%rare
CADD: 3.358
ClinVar Submissions (6)
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Last Evaluated: Jan 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42930725
Last Evaluated: Jan 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42930725
GLUT1 deficiency syndrome is a disorder affecting the nervous system that can have a variety of neurological signs and symptoms. Approximately 90 percent of affected individuals have a form of the disorder often referred to as common GLUT1 deficiency syndrome. These individuals generally have frequent seizures (epilepsy) beginning in the first months of life. In newborns, the first sign of the disorder may be involuntary eye movements that are rapid and irregular. Babies with common GLUT1 deficiency syndrome have a normal head size at birth, but growth of the brain and skull is often slow, which can result in an abnormally small head size (microcephaly). People with this form of GLUT1 deficiency syndrome may have developmental delay or intellectual disability. Most affected individuals also have other neurological problems, such as stiffness caused by abnormal tensing of the muscles (spasticity), difficulty in coordinating movements (ataxia), and speech difficulties (dysarthria). Some experience episodes of confusion, lack of energy (lethargy), headaches, or muscle twitches (myoclonus), particularly during periods without food (fasting).About 10 percent of individuals with GLUT1 deficiency syndrome have a form of the disorder often known as non-epileptic GLUT1 deficiency syndrome, which is usually less severe than the common form. People with the non-epileptic form do not have seizures, but they may still have developmental delay and intellectual disability. Most have movement problems such as ataxia or involuntary tensing of various muscles (dystonia); the movement problems may be more pronounced than in the common form.Several conditions that were originally given other names have since been recognized to be variants of GLUT1 deficiency syndrome. These include paroxysmal choreoathetosis with spasticity (dystonia 9); paroxysmal exercise-induced dyskinesia and epilepsy (dystonia 18); and certain types of epilepsy. In rare cases, people with variants of GLUT1 deficiency syndrome produce abnormal red blood cells and have uncommon forms of a blood condition known as anemia, which is characterized by a shortage of red blood cells.
Last Evaluated: Jan 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42930725
Last Evaluated: Jan 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42930725
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:42930725
Benign/Likely benign
Hetero
Gene:
RAI1
Variant:
c.4512G>T
(p.Leu1504=)
rsID: rs117995220
Ref Allele: G
Alt Allele: T
Freq: 0.5153%rare
CADD: 8.328
ClinVar Submissions (5)
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:17797460
Smith-Magenis syndrome (SMS) is characterized by distinctive physical features (particularly facial features that progress with age), developmental delay, cognitive impairment, and behavioral abnormalities. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. The majority of individuals function in the mild-to-moderate range of intellectual disability. The behavioral phenotype, including significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until age 18 months or older and continues to change until adulthood. Sensory integration issues are frequently noted. Children and adults typically have inattention, distractibility, hyperactivity, impulsivity, maladaptive behaviors including frequent outbursts/temper tantrums, attention seeking, disobedience, aggression, toileting difficulties, and self-injurious behaviors (SIB) including self-hitting, self-biting, and/or skin picking, inserting foreign objects into body orifices (polyembolokoilamania), and yanking fingernails and/or toenails (onychotillomania). Among the stereotypic behaviors described, the spasmodic upper-body squeeze or "self-hug" seems to be highly associated with SMS. The finger lick and page flipping ("lick and flip") behavior may be less prevalent than initially reported. An underlying developmental asynchrony, specifically between intellectual functioning and emotional maturity, may also contribute to maladaptive behaviors in people with SMS.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:17797460
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:17797460
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:17797460
Benign
Hetero
Gene:
COL3A1
Variant:
c.1804C>A
(p.Pro602Thr)
rsID: rs35795890
Ref Allele: C
Alt Allele: A
Freq: 0.5169%rare
CADD: 20.4
ClinVar Submissions (8)
Last Evaluated: Jan 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:188997207
Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising; characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes); and an aged appearance to the extremities, particularly the hands. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – are most often present in those children ascertained without a major complication.
Last Evaluated: Jan 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:188997207
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:188997207
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:188997207
Benign/Likely benign
Hetero
Gene:
F7
Variant:
c.806-10T>C
rsID: rs3093266
Ref Allele: T
Alt Allele: C
Freq: 0.5192%rare
CADD: 3.057
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 01, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:113118403
Likely benign
Hetero
Gene:
APBA2
Variant:
c.1815G>A
(p.Pro605=)
rsID: rs140055297
Ref Allele: G
Alt Allele: A
Freq: 0.5192%rare
CADD: 0.045
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 25, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:29106717
Likely benign
Hetero
Gene:
NOTCH1
Variant:
c.5124G>T
(p.Ser1708=)
rsID: rs35980907
Ref Allele: C
Alt Allele: A
Freq: 0.5288%rare
CADD: 8.62
ClinVar Submissions (4)
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136503225
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136503225
A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides.
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136503225
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136503225
Benign/Likely benign
Hetero
Gene:
IL10RA
Variant:
c.21G>C
(p.Val7=)
rsID: rs4252301
Ref Allele: G
Alt Allele: C
Freq: 0.5439%rare
CADD: 16.85
ClinVar Submissions (2)
Last Evaluated: Jan 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:117986488
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:117986488
Benign
Hetero
Gene:
MEFV
Variant:
c.*639G>A
rsID: rs181380218
Ref Allele: C
Alt Allele: T
Freq: 0.5439%rare
CADD: 2.53
ClinVar Submissions (1)
Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2. FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication, if untreated. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:3242502
Conflicting/Uncertain
Hetero
Gene:
ECEL1
Variant:
c.51C>A
(p.Val17=)
rsID: rs191331240
Ref Allele: G
Alt Allele: T
Freq: 0.5543%rare
CADD: 8.505
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:232486603
Likely benign
Hetero
Gene:
HBA2
Variant:
c.*107A>G
rsID: rs2541640
Ref Allele: A
Alt Allele: G
Freq: 0.5559%rare
CADD: 4.523
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 25, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:173707
Benign
Hetero
Gene:
LOX
Variant:
c.476C>A
(p.Pro159Gln)
rsID: rs41407546
Ref Allele: G
Alt Allele: T
Freq: 0.5837%rare
CADD: 11.27
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:122077510
Benign/Likely benign
Hetero
Gene:
TTC7A
Variant:
c.649-10C>T
rsID: rs149360779
Ref Allele: C
Alt Allele: T
Freq: 0.5933%rare
CADD: 11.88
ClinVar Submissions (3)
Gastrointestinal defects and immunodeficiency syndrome (GIDID) is characterized by multiple intestinal atresia, in which atresia occurs at various levels throughout the small and large intestines. Surgical outcomes are poor, and the condition is usually fatal within the first month of life. Some patients exhibit inflammatory bowel disease (IBD), with or without intestinal atresia, and in some cases, the intestinal features are associated with either mild or severe combined immunodeficiency (Samuels et al., 2013; Avitzur et al., 2014; Lemoine et al., 2014).
Last Evaluated: Jan 08, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:46978782
Benign/Likely benign
Homo
Gene:
CACNA2D1
Variant:
c.1144-18A>G
rsID: rs78174406
Ref Allele: T
Alt Allele: C
Freq: 0.5933%rare
CADD: 0.163
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 20, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:82014497
Benign
Hetero
Gene:
POLR3A
Variant:
c.*90G>A
rsID: rs146055367
Ref Allele: C
Alt Allele: T
Freq: 0.6108%rare
CADD: 2.52
ClinVar Submissions (1)
POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:77977388
Conflicting/Uncertain
Hetero
Gene:
FREM2
Variant:
c.*1539C>T
rsID: rs41286131
Ref Allele: C
Alt Allele: T
Freq: 0.6315%rare
CADD: 1.11
ClinVar Submissions (1)
Fraser syndrome is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract (summary by van Haelst et al., 2008). Genetic Heterogeneity of Fraser Syndrome Fraser syndrome-2 (FRASRS2) is caused by mutation in the FREM2 gene (608945) on chromosome 13q13, and Fraser syndrome-3 (FRASRS3) is caused by mutation in the GRIP1 gene (604597) on chromosome 12q14. See Bowen syndrome (211200) for a comparable but probably distinct syndrome of multiple congenital malformations.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 13:38882326
Conflicting/Uncertain
Hetero
Gene:
COL12A1
Variant:
c.6590C>T
(p.Thr2197Ile)
rsID: rs117038107
Ref Allele: G
Alt Allele: A
Freq: 0.6363%rare
CADD: 15.18
ClinVar Submissions (1)
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:75125144
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:75125144
Benign
Hetero
Gene:
ALX4
Variant:
c.*290T>C
rsID: rs7128671
Ref Allele: A
Alt Allele: G
Freq: 0.6419%rare
CADD: 9.452
ClinVar Submissions (1)
Enlarged parietal foramina is an inherited condition of impaired skull development. It is characterized by enlarged openings (foramina) in the parietal bones, which are the two bones that form the top and sides of the skull. This condition is due to incomplete bone formation (ossification) within the parietal bones. The openings are symmetrical and circular in shape, ranging in size from a few millimeters to several centimeters wide. Parietal foramina are a normal feature of fetal development, but typically they close before the baby is born, usually by the fifth month of pregnancy. However, in people with this condition, the parietal foramina remain open throughout life.The enlarged parietal foramina are soft to the touch due to the lack of bone at those areas of the skull. People with enlarged parietal foramina usually do not have any related health problems; however, scalp defects, seizures, and structural brain abnormalities have been noted in a small percentage of affected people. Pressure applied to the openings can lead to severe headaches, and individuals with this condition have an increased risk of brain damage or skull fractures if any trauma is experienced in the area of the openings.There are two forms of enlarged parietal foramina, called type 1 and type 2, which differ in their genetic cause.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:44264564
Likely benign
Hetero
Gene:
CDH23
Variant:
c.1096G>A
(p.Ala366Thr)
rsID: rs143282422
Ref Allele: G
Alt Allele: A
Freq: 0.6753%rare
CADD: 25.6
ClinVar Submissions (5)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 16, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:71617355
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 16, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:71617355
Benign/Likely benign
Hetero
Gene:
PLEC
Variant:
c.5558G>A
(p.Arg1853Gln)
rsID: rs147838690
Ref Allele: C
Alt Allele: T
Freq: 0.6761%rare
CADD: 14.1
ClinVar Submissions (6)
Epidermolysis bullosa simplex with muscular dystrophy is an autosomal recessive disorder characterized by early childhood onset of progressive muscular dystrophy and blistering skin changes (Fine et al., 1989). Fine et al. (1991) reported a revised classification of the subtypes of inherited epidermolysis bullosa. In reports of 2 consensus meetings on EB, Fine et al. (2000, 2008) referred to EB with muscular dystrophy due to PLEC1 mutations as a form of basal simplex EB. Fine et al. (2000, 2008) also eliminated the term 'hemidesmosomal,' which had previously been proposed for this entity (Uitto et al., 1997) because ultrastructural analysis can demonstrate tissue abnormalities of the hemidesmosomes.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:143924452
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:143924452
EBSPA is an autosomal recessive genodermatosis characterized by severe skin blistering at birth and congenital pyloric atresia. Death usually occurs in infancy. In reports of 2 consensus meetings for EB, Fine et al. (2000, 2008) considered EBSPA to be a 'basal' form of simplex EB because the electron microscopy shows that skin cleavage occurs in the lower basal level of the keratinocyte, just above the hemidesmosome. There is often decreased integration of keratin filaments with hemidesmosomes.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:143924452
Epidermolysis bullosa simplex is one of a group of genetic conditions called epidermolysis bullosa that cause the skin to be very fragile and to blister easily. Blisters and areas of skin loss (erosions) occur in response to minor injury or friction, such as rubbing or scratching. Epidermolysis bullosa simplex is one of the major forms of epidermolysis bullosa. The signs and symptoms of this condition vary widely among affected individuals. Blistering primarily affects the hands and feet in mild cases, and the blisters usually heal without leaving scars. Severe cases of this condition involve widespread blistering that can lead to infections, dehydration, and other medical problems. Severe cases may be life-threatening in infancy.Researchers have identified four major types of epidermolysis bullosa simplex. Although the types differ in severity, their features overlap significantly, and they are caused by mutations in the same genes. Most researchers now consider the major forms of this condition to be part of a single disorder with a range of signs and symptoms.The mildest form of epidermolysis bullosa simplex, known as the localized type (formerly called the Weber-Cockayne type), is characterized by skin blistering that begins anytime between childhood and adulthood and is usually limited to the hands and feet. Later in life, skin on the palms of the hands and soles of the feet may thicken and harden (hyperkeratosis).The Dowling-Meara type is the most severe form of epidermolysis bullosa simplex. Extensive, severe blistering can occur anywhere on the body, including the inside of the mouth, and blisters may appear in clusters. Blistering is present from birth and tends to improve with age. Affected individuals also experience abnormal nail growth and hyperkeratosis of the palms and soles.Another form of epidermolysis bullosa simplex, known as the other generalized type (formerly called the Koebner type), is associated with widespread blisters that appear at birth or in early infancy. The blistering tends to be less severe than in the Dowling-Meara type.Epidermolysis bullosa simplex with mottled pigmentation is characterized by patches of darker skin on the trunk, arms, and legs that fade in adulthood. This form of the disorder also involves skin blistering from early infancy, hyperkeratosis of the palms and soles, and abnormal nail growth.In addition to the four major types described above, researchers have identified another skin condition related to epidermolysis bullosa simplex, which they call the Ogna type. It is caused by mutations in a gene that is not associated with the other types of epidermolysis bullosa simplex. It is unclear whether the Ogna type is a subtype of epidermolysis bullosa simplex or represents a separate form of epidermolysis bullosa.Several other variants of epidermolysis bullosa simplex have been proposed, but they appear to be very rare.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:143924452
Autosomal recessive limb-girdle muscular dystrophy-17 is characterized by early childhood onset of proximal muscle weakness and atrophy without skin involvement. One family has shown rapid progression of the disorder in adolescence (summary by Gundesli et al., 2010). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:143924452
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:143924452
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:143924452
Benign
Hetero
Gene:
MTIF3
Variant:
c.413A>G
(p.Gln138Arg)
rsID: rs140262959
Ref Allele: T
Alt Allele: C
Freq: 0.6992%rare
CADD: 22.7
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:27440036
Likely benign
Hetero
Gene:
CTH
Variant:
c.200C>T
(p.Thr67Ile)
rsID: rs28941785
Ref Allele: C
Alt Allele: T
Freq: 0.7008%rare
CADD: 25.2
ClinVar Submissions (3)
Cystathioninuria, an autosomal recessive phenotype with no striking pathologic features, is characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Because of the inconsistency and wide variety of disease associations, cystathioninuria is considered to be a benign biochemical anomaly (Mudd et al., 2001).
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:70415987
OMIM Allelic Variant: 607657.0003
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:70415987
OMIM Allelic Variant: 607657.0003
Low clinical importance, pathogenic — Causes cystathioninuria in a recessive manner (an abnormal accumulation of cystathione in urine). Generally thought to be a benign anomaly, it's often only found when a clinician performs biochemical assays for investigating an unrelated disease.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
HPS3
Variant:
c.*170C>T
rsID: rs182666670
Ref Allele: C
Alt Allele: T
Freq: 0.7175%rare
CADD: 0.995
ClinVar Submissions (1)
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:149172392
Conflicting/Uncertain
Hetero
Gene:
DPYS
Variant:
c.1029C>G
(p.Thr343=)
rsID: rs117104587
Ref Allele: G
Alt Allele: C
Freq: 0.7239%rare
CADD: 2.103
ClinVar Submissions (2)
DPYS deficiency is an autosomal recessive disease characterized by the presence of dihydropyrimidinuria. The clinical phenotype is highly variable, ranging from early infantile onset of severe neurologic involvement, dysmorphic features, and feeding problems to late onset of mild intellectual disability and even asymptomatic individuals. Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of the anticancer drug 5-fluorouracil (5-FU) (summary by Nakajima et al., 2017). See also dihydropyrimidine dehydrogenase deficiency (274270), a similar disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:104428043
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:104428043
Conflicting/Uncertain
Hetero
Gene:
SZT2
Variant:
c.7040-13C>G
rsID: rs116454519
Ref Allele: C
Alt Allele: G
Freq: 0.7287%rare
CADD: 5.402
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:43440440
Benign
Hetero
Gene:
A2ML1
Variant:
c.861C>A
(p.Asp287Glu)
rsID: rs61921916
Ref Allele: C
Alt Allele: A
Freq: 0.7311%rare
CADD: 14.75
ClinVar Submissions (4)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:8838341
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:8838341
Benign
Hetero
Gene:
CC2D1A
Variant:
c.566C>T
(p.Ala189Val)
rsID: rs61740117
Ref Allele: C
Alt Allele: T
Freq: 0.7319%rare
CADD: 15.62
ClinVar Submissions (2)
Last Evaluated: Nov 30, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 19:13913456
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 30, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 19:13913456
Likely benign
Hetero
Gene:
ALX4
Variant:
c.63C>T
(p.Tyr21=)
rsID: rs61737298
Ref Allele: G
Alt Allele: A
Freq: 0.7462%rare
CADD: 22
ClinVar Submissions (1)
Enlarged parietal foramina is an inherited condition of impaired skull development. It is characterized by enlarged openings (foramina) in the parietal bones, which are the two bones that form the top and sides of the skull. This condition is due to incomplete bone formation (ossification) within the parietal bones. The openings are symmetrical and circular in shape, ranging in size from a few millimeters to several centimeters wide. Parietal foramina are a normal feature of fetal development, but typically they close before the baby is born, usually by the fifth month of pregnancy. However, in people with this condition, the parietal foramina remain open throughout life.The enlarged parietal foramina are soft to the touch due to the lack of bone at those areas of the skull. People with enlarged parietal foramina usually do not have any related health problems; however, scalp defects, seizures, and structural brain abnormalities have been noted in a small percentage of affected people. Pressure applied to the openings can lead to severe headaches, and individuals with this condition have an increased risk of brain damage or skull fractures if any trauma is experienced in the area of the openings.There are two forms of enlarged parietal foramina, called type 1 and type 2, which differ in their genetic cause.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:44310000
Likely benign
Hetero
Gene:
BIN1
Variant:
c.1625A>G
(p.Lys542Arg)
rsID: rs138047593
Ref Allele: T
Alt Allele: C
Freq: 0.759%rare
CADD: 25.4
ClinVar Submissions (5)
Centronuclear myopathy is a condition characterized by muscle weakness (myopathy) and wasting (atrophy) in the skeletal muscles, which are the muscles used for movement. The severity of centronuclear myopathy varies among affected individuals, even among members of the same family.People with centronuclear myopathy begin experiencing muscle weakness at any time from birth to early adulthood. The muscle weakness slowly worsens over time and can lead to delayed development of motor skills, such as crawling or walking; muscle pain during exercise; and difficulty walking. Some affected individuals may need wheelchair assistance as the muscles atrophy and weakness becomes more severe. In rare instances, the muscle weakness improves over time.Some people with centronuclear myopathy experience mild to severe breathing problems related to the weakness of muscles needed for breathing. People with centronuclear myopathy may have droopy eyelids (ptosis) and weakness in other facial muscles, including the muscles that control eye movement. People with this condition may also have foot abnormalities, a high arch in the roof of the mouth (high-arched palate), and abnormal side-to-side curvature of the spine (scoliosis). Rarely, individuals with centronuclear myopathy have a weakened heart muscle (cardiomyopathy), disturbances in nerve function (neuropathy), or intellectual disability.A key feature of centronuclear myopathy is the displacement of the nucleus in muscle cells, which can be viewed under a microscope. Normally the nucleus is found at the edges of the rod-shaped muscle cells, but in people with centronuclear myopathy the nucleus is located in the center of these cells. How the change in location of the nucleus affects muscle cell function is unknown.
Last Evaluated: May 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:127050470
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:127050470
Benign
Hetero
Gene:
ATP2B3
Variant:
c.3052-5C>T
rsID: rs189012896
Ref Allele: C
Alt Allele: T
Freq: 0.7645%rare
ClinVar Submissions (1)
SCAX1 is an X-linked recessive neurologic disorder characterized by hypotonia at birth, delayed motor development, gait ataxia, difficulty standing, dysarthria, and slow eye movements. Brain MRI shows cerebellar ataxia (summary by Bertini et al., 2000). Genetic Heterogeneity of X-linked Spinocerebellar Ataxia X-linked recessive spinocerebellar ataxia (SCAX) is a clinically and genetically heterogeneous disorder. See also SCAX2 (302600), SCAX3 (301790), SCAX4 (301840), and SCAX5 (300703).
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:153562130
Benign
Hetero
Gene:
FREM2
Variant:
c.*3731A>C
rsID: rs41286133
Ref Allele: A
Alt Allele: C
Freq: 0.7709%rare
CADD: 7.201
ClinVar Submissions (1)
Fraser syndrome is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract (summary by van Haelst et al., 2008). Genetic Heterogeneity of Fraser Syndrome Fraser syndrome-2 (FRASRS2) is caused by mutation in the FREM2 gene (608945) on chromosome 13q13, and Fraser syndrome-3 (FRASRS3) is caused by mutation in the GRIP1 gene (604597) on chromosome 12q14. See Bowen syndrome (211200) for a comparable but probably distinct syndrome of multiple congenital malformations.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 13:38884518
Conflicting/Uncertain
Hetero
Gene:
ANO5
Variant:
c.2387C>T
(p.Ser796Leu)
rsID: rs61910685
Ref Allele: C
Alt Allele: T
Freq: 0.7733%rare
CADD: 11.68
ClinVar Submissions (6)
Gnathodiaphyseal dysplasia is an autosomal dominant generalized skeletal syndrome characterized by cementoosseous lesions of the jawbones, in conjunction with bone fragility, bowing/cortical thickening of tubular bones, and diaphyseal sclerosis of long bones (summary by Marconi et al., 2013).
Last Evaluated: Jan 04, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:22274720
The spectrum of ANO5-related muscle diseases is a continuum that ranges from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. The most typical presentation is limb-girdle muscular dystrophy type 2L (LGMD2L) with late-onset proximal lower-limb weakness (mean onset age 35 years; range 15-70 years). Less common is Miyoshi-like disease or Miyoshi muscular dystrophy 3 with early-adult-onset calf distal myopathy (age 20 to 25 years). Incidental hyperCKemia may be present even earlier. Females have milder disease manifestations than males. Initial symptoms are walking difficulties, reduced sports performance, and difficulties in standing on toes as well as nonspecific exercise myalgia and/or burning sensation in the calf muscles. Muscle weakness and atrophy are frequently asymmetric. Bulbar or respiratory symptoms have not been reported. Disease progression is slow in both the LGMD and distal forms; ambulation is preserved until very late in the disease course.
Last Evaluated: Jan 04, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:22274720
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 04, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:22274720
Benign/Likely benign
Hetero
Gene:
ANK2
Variant:
c.9854T>C
(p.Ile3285Thr)
rsID: rs36210417
Ref Allele: T
Alt Allele: C
Freq: 0.7797%rare
CADD: 24.1
ClinVar Submissions (8)
Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the ECG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7), hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8), and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:113358472
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:113358472
A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:113358472
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:113358472
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:113358472
Benign/Likely benign
Hetero
Gene:
APOB
Variant:
c.1352+60C>A
rsID: rs12714224
Ref Allele: G
Alt Allele: T
Freq: 0.7876%rare
CADD: 0.546
ClinVar Submissions (1)
Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.
Last Evaluated: Mar 01, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:21032294
Conflicting/Uncertain
Hetero
Gene:
COQ8B
Variant:
c.1578C>T
(p.Asp526=)
rsID: rs56276635
Ref Allele: G
Alt Allele: A
Freq: 0.8131%rare
CADD: 10.25
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 08, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:40692092
Benign
Hetero
Gene:
SCN11A
Variant:
c.4683G>C
(p.Leu1561=)
rsID: rs41285131
Ref Allele: C
Alt Allele: G
Freq: 0.8577%rare
CADD: 1.029
ClinVar Submissions (1)
Familial episodic pain syndrome is an autosomal dominant disorder characterized by early childhood onset of intense episodic pain mainly affecting the distal lower extremities, but sometimes affecting the upper extremities as well. The pain comes in cycles lasting several days, is exacerbated by fatigue, may be accompanied by sweating, and can be relieved by antiinflammatory medication. Severe episodic pain tends to diminish with age (summary by Zhang et al., 2013). For a discussion of the genetic heterogeneity of familial episodic pain syndrome, see FEPS1 (615040).
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:38847387
A very rare disorder caused by mutation in the SCN11A gene. Affected individuals are unable to experience pain since birth resulting in self-inflicted injuries.
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:38847387
Benign
Hetero
Gene:
POF1B
Variant:
c.*775G>T
rsID: rs147030302
Ref Allele: C
Alt Allele: A
Freq: 0.8577%rare
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: X:85278646
Likely benign
Hetero
Gene:
ATR
Variant:
c.891G>C
(p.Lys297Asn)
rsID: rs2229033
Ref Allele: C
Alt Allele: G
Freq: 0.8609%rare
CADD: 15.18
ClinVar Submissions (3)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Oct 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:142562511
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:142562511
Benign/Likely benign
Hetero
Gene:
MAP2K2
Variant:
c.303+18G>A
rsID: rs116988721
Ref Allele: C
Alt Allele: T
Freq: 0.8633%rare
CADD: 0.212
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:4117401
Benign
Hetero
Gene:
SLC4A11
Variant:
c.2439T>G
(p.Thr813=)
rsID: rs7262506
Ref Allele: A
Alt Allele: C
Freq: 0.8641%rare
CADD: 1.389
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 20:3228426
Conflicting/Uncertain
Hetero
Gene:
CNNM2
Variant:
c.*904G>C
rsID: rs145537350
Ref Allele: G
Alt Allele: C
Freq: 0.8912%rare
CADD: 9.688
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:103078084
Likely benign
Hetero
Gene:
KMT2D
Variant:
c.7670C>T
(p.Pro2557Leu)
rsID: rs189888707
Ref Allele: G
Alt Allele: A
Freq: 0.8943%rare
CADD: 23.3
ClinVar Submissions (8)
Kabuki syndrome is a disorder that affects many parts of the body. It is characterized by distinctive facial features including arched eyebrows; long eyelashes; long openings of the eyelids (long palpebral fissures) with the lower lids turned out (everted) at the outside edges; a flat, broadened tip of the nose; and large protruding earlobes. The name of this disorder comes from the resemblance of its characteristic facial appearance to stage makeup used in traditional Japanese Kabuki theater.People with Kabuki syndrome have mild to severe developmental delay and intellectual disability. Affected individuals may also have seizures, an unusually small head size (microcephaly), or weak muscle tone (hypotonia). Some have eye problems such as rapid, involuntary eye movements (nystagmus) or eyes that do not look in the same direction (strabismus).Other characteristic features of Kabuki syndrome include short stature and skeletal abnormalities such as abnormal side-to-side curvature of the spine (scoliosis), short fifth (pinky) fingers, or problems with the hip and knee joints. The roof of the mouth may have an abnormal opening (cleft palate) or be high and arched, and dental problems are common in affected individuals. People with Kabuki syndrome may also have fingerprints with unusual features and fleshy pads at the tips of the fingers. These prominent finger pads are called fetal finger pads because they normally occur in human fetuses; in most people they disappear before birth.A wide variety of other health problems occur in some people with Kabuki syndrome. Among the most commonly reported are heart abnormalities, frequent ear infections (otitis media), hearing loss, and early puberty.
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:49040100
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:49040100
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:49040100
Benign/Likely benign
Hetero
Gene:
SCN1B
Variant:
c.591-14C>A
rsID: rs28365109
Ref Allele: C
Alt Allele: A
Freq: 0.9039%rare
CADD: 12.25
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:35039621
Benign
Hetero
Gene:
TRAPPC11
Variant:
c.145G>C
(p.Val49Leu)
rsID: rs141909783
Ref Allele: G
Alt Allele: C
Freq: 0.9222%rare
CADD: 23.2
ClinVar Submissions (2)
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:183664012
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:183664012
Benign
Hetero
Gene:
CACNA1S
Variant:
c.3261A>G
(p.Gln1087=)
rsID: rs34515088
Ref Allele: T
Alt Allele: C
Freq: 0.9397%rare
CADD: 18.16
ClinVar Submissions (5)
Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP.
Last Evaluated: Jan 22, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201060811
Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP.
Last Evaluated: Jan 22, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201060811
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.
Last Evaluated: Jan 22, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201060811
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.
Last Evaluated: Jan 22, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201060811
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 22, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201060811
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 22, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201060811
Benign/Likely benign
Hetero
Gene:
TSEN2
Variant:
c.-220G>A
rsID: rs182837891
Ref Allele: G
Alt Allele: A
Freq: 0.9437%rare
CADD: 6.987
ClinVar Submissions (1)
Pontocerebellar hypoplasia is a group of related conditions that affect the development of the brain. The term "pontocerebellar" refers to the pons and the cerebellum, which are the brain structures that are most severely affected in many forms of this disorder. The pons is located at the base of the brain in an area called the brainstem, where it transmits signals between the cerebellum and the rest of the brain. The cerebellum, which is located at the back of the brain, normally coordinates movement. The term "hypoplasia" refers to the underdevelopment of these brain regions.Pontocerebellar hypoplasia also causes impaired growth of other parts of the brain, leading to an unusually small head size (microcephaly). This microcephaly is usually not apparent at birth but becomes noticeable as brain growth continues to be slow in infancy and early childhood.Researchers have described at least ten types of pontocerebellar hypoplasia. All forms of this condition are characterized by impaired brain development, delayed development overall, problems with movement, and intellectual disability. The brain abnormalities are usually present at birth, and in some cases they can be detected before birth. Many children with pontocerebellar hypoplasia live only into infancy or childhood, although some affected individuals have lived into adulthood.The two major forms of pontocerebellar hypoplasia are designated as type 1 (PCH1) and type 2 (PCH2). In addition to the brain abnormalities described above, PCH1 causes problems with muscle movement resulting from a loss of specialized nerve cells called motor neurons in the spinal cord, similar to another genetic disorder known as spinal muscular atrophy. Individuals with PCH1 also have very weak muscle tone (hypotonia), joint deformities called contractures, vision impairment, and breathing and feeding problems that are evident from early infancy.Common features of PCH2 include a lack of voluntary motor skills (such as grasping objects, sitting, or walking), problems with swallowing (dysphagia), and an absence of communication, including speech. Affected children typically develop temporary jitteriness (generalized clonus) in early infancy, abnormal patterns of movement described as chorea or dystonia, and stiffness (spasticity). Many also have impaired vision and seizures.The other forms of pontocerebellar hypoplasia, designated as type 3 (PCH3) through type 10 (PCH10), appear to be rare and have each been reported in only a small number of individuals. Because the different types have overlapping features, and some are caused by mutations in the same genes, researchers have proposed that the types be considered as a spectrum instead of distinct conditions.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:12484678
Conflicting/Uncertain
Hetero
Gene:
ADH1C
Variant:
c.232G>T
(p.Gly78Ter)
rsID: rs283413
Ref Allele: C
Alt Allele: A
Freq: 0.9525%rare
CADD: 41
ClinVar Submissions (1)
Parkinsonism refers to all clinical states characterized by tremor, muscle rigidity, slowed movement (bradykinesia) and often postural instability. Parkinson disease is the primary and most common form of parkinsonism. Psychiatric manifestations, which include depression and visual hallucinations, are common but not uniformly present. Dementia eventually occurs in at least 20% of cases. The most common sporadic form of Parkinson disease manifests around age 60; however, young-onset and even juvenile presentations are seen.
Last Evaluated: Jan 01, 2005
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: risk factor
Assembly: GRCh38
Chromosome/Position: 4:99347033
OMIM Allelic Variant: 103730.0003
Hetero
Gene:
FUT6
Variant:
c.945C>A
(p.Tyr315Ter)
rsID: rs145035679
Ref Allele: G
Alt Allele: T
Freq: 0.9612%rare
CADD: 42
ClinVar Submissions (2)
Last Evaluated: Jan 26, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:5831623
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 26, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:5831623
Conflicting/Uncertain
Homo
Gene:
PAX9
Variant:
c.516G>A
(p.Lys172=)
rsID: rs61734510
Ref Allele: G
Alt Allele: A
Freq: 0.9835%rare
CADD: 22.4
ClinVar Submissions (2)
Tooth agenesis in some form is a common human anomaly that affects approximately 20% of the population. Although tooth agenesis is associated with numerous syndromes, several case reports describe nonsyndromic forms that are either sporadic or familial in nature, as reviewed by Gorlin et al. (1990). The incidence of familial tooth agenesis varies with each class of teeth. Most commonly affected are third molars (wisdom teeth), followed by either upper lateral incisors or lower second premolars; agenesis involving first and second molars is very rare. Also see 114600 and 302400. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). Faulty use of the terms, however, have confounded their use. The term 'partial anodontia' is obsolete (Salinas, 1978). Genetic Heterogeneity of Selective Tooth Agenesis Other forms of selective tooth agenesis include STHAG2 (602639), mapped to chromosome 16q12; STHAG3 (604625), caused by mutation in the PAX9 gene (167416) on chromosome 14q12; STHAG4 (150400), caused by mutation in the WNT10A gene (606268) on chromosome 2q35; STHAG5 (610926), mapped to chromosome 10q11; STHAG7 (616724), caused by mutation in the LRP6 gene (603507) on chromosome 12p13; STHAG8 (617073), caused by mutation in the WNT10B gene (601906) on chromosome 12q13; STHAG9 (617275), caused by mutation in the GREM2 gene (608832) on chromosome 1q43; and STHAGX1 (313500), caused by mutation in the EDA gene (300451) on chromosome Xq13. A type of selective tooth agenesis that was formerly designated STHAG6 has been incorporated into the dental anomalies and short stature syndrome (DASS; 601216). Of 34 unrelated patients with nonsyndromic tooth agenesis, van den Boogaard et al. (2012) found that 56% (19 patients) had mutations in the WNT10A gene (STHAG4), whereas only 3% and 9% had mutations in the MSX1 (STHAG1) and PAX9 (STHAG3) genes, respectively. The authors concluded that WNT10A is a major gene in the etiology of isolated hypodontia. Genotype-Phenotype Correlations Yu et al. (2016) observed that the most frequently missing permanent teeth in WNT10B-associated oligodontia were the lateral incisors (83.3%), whereas premolars were missing only 51.4% of the time, which they noted was a pattern 'clearly different' from the oligodontia patterns resulting from WNT10A mutations. They also stated that the selective pattern in WNT10B mutants was different from that associated with mutations in other genes, such as MSX1, in which second premolars are missing, and PAX9, in which there is agenesis of molars.
Last Evaluated: Oct 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:36663408
Agenesis specifically affecting one of the classes incisor, premolar, or molar.
Last Evaluated: Oct 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:36663408
Benign/Likely benign
Hetero
Below are uncommon mutations (frequency between 1% and 5%) found in ClinVar. The data presented has no guarantees of reporting accuracy. Heterozygous variants are repoted as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
BRCA2
Variant:
c.8332-2438C>T
rsID: rs139834007
Ref Allele: C
Alt Allele: T
Freq: 1.0003%uncommon
CADD: 0.426
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Jan 12, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32367964
Expert Reviewed Benign
Hetero
Gene:
RP1L1
Variant:
c.130C>G
(p.Pro44Ala)
rsID: rs140397694
Ref Allele: G
Alt Allele: C
Freq: 1.0019%uncommon
CADD: 15.42
ClinVar Submissions (1)
Occult macular dystrophy is characterized by progressive decline of visual acuity in both eyes, associated with a normal fundus and normal fluorescein angiography. Patients have normal full-field electroretinograms (ERGs) but severely reduced focal macular ERGs, as recorded by conventional techniques using small stimuli under background illumination. OCMD patients are believed to have localized retinal dysfunction distal to the ganglion cells in the central retina (summary by Piao et al., 2000).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:10623072
Likely benign
Hetero
Gene:
RIN2
Variant:
c.85G>A
(p.Gly29Arg)
rsID: rs78648341
Ref Allele: G
Alt Allele: A
Freq: 1.0106%uncommon
CADD: 28
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 07, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 20:19935126
Benign
Hetero
Gene:
SH3TC2
Variant:
c.*10767G>A
rsID: rs139720866
Ref Allele: C
Alt Allele: T
Freq: 1.0242%uncommon
CADD: 0.702
ClinVar Submissions (1)
Charcot-Marie-Tooth disease type 4 (CMT4) belongs to the genetically heterogeneous group of CMT peripheral sensorimotor polyneuropathy diseases. Type 4 is less common and often limited to certain ethnic groups. Patients present with the typical CMT phenotype along with typical features of progressive, distally accentuated weakness and atrophy of muscles innervated by the peroneal nerve in the lower limbs, followed by weakness and atrophy of hands, sensory loss, and characteristic foot abnormalities.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:148993944
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:148993944
Conflicting/Uncertain
Hetero
Gene:
TPRN
Variant:
c.858C>T
(p.Cys286=)
rsID: rs375619082
Ref Allele: G
Alt Allele: A
Freq: 1.0305%uncommon
CADD: 19.69
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:137199854
Benign/Likely benign
Hetero
Gene:
CCDC88C
Variant:
c.5948G>C
(p.Gly1983Ala)
rsID: rs45542736
Ref Allele: C
Alt Allele: G
Freq: 1.0305%uncommon
CADD: 13.56
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 08, 2013
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:91272764
Benign
Hetero
Gene:
GNE
Variant:
c.*2211C>G
rsID: rs150978860
Ref Allele: G
Alt Allele: C
Freq: 1.0393%uncommon
CADD: 6.291
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:36215154
GNE-related myopathy, also known as inclusion body myopathy 2, is characterized by slowly progressive distal muscle weakness that begins in the late teens to early adult years with gait disturbance and foot drop secondary to anterior tibialis muscle weakness. Weakness eventually includes the hand and thigh muscles but commonly spares the quadriceps muscles, even in advanced disease. Affected individuals are usually wheelchair bound about 20 years after onset. If quadriceps sparing is incomplete, loss of ambulation tends to occur earlier.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:36215154
Sialuria is a rare inborn error of metabolism in which excessive free sialic acid is synthesized. Clinical features include hepatosplenomegaly, coarse facial features, and varying degrees of developmental delay (summary by Enns et al., 2001).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:36215154
Likely benign
Hetero
Gene:
CHMP2B
Variant:
c.*231T>C
rsID: rs17189270
Ref Allele: T
Alt Allele: C
Freq: 1.0496%uncommon
CADD: 8.999
ClinVar Submissions (1)
Frontotemporal dementia (FTD) refers to a clinical manifestation of the pathologic finding of frontotemporal lobar degeneration (FTLD). FTD, the most common subtype of FTLD, is a behavioral variant characterized by changes in social and personal conduct with loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output. A second clinical subtype of FTLD is 'semantic dementia,' characterized by specific loss of comprehension of language and impaired facial and object recognition. A third clinical subtype of FTLD is 'primary progressive aphasia' (PPA), characterized by a reduction in speech production, speech errors, and word retrieval difficulties resulting in mutism and an inability to communicate. All subtypes have relative preservation of memory, at least in the early stages. FTLD is often associated with parkinsonism or motor neuron disease (MND) resembling amyotrophic lateral sclerosis (ALS; 105400) (reviews by Tolnay and Probst, 2002 and Mackenzie and Rademakers, 2007). Mackenzie et al. (2009, 2010) provided a classification of FTLD subtypes according to the neuropathologic findings (see PATHOGENESIS below). Clinical Variability of Tauopathies Tauopathies comprise a clinically variable group of neurodegenerative diseases characterized neuropathologically by accumulation of abnormal MAPT-positive inclusions in nerve and/or glial cells. In addition to frontotemporal dementia, semantic dementia, and PPA, different clinical syndromes with overlapping features have been described, leading to confusion in the terminology (Tolnay and Probst, 2002). Other terms used historically include parkinsonism and dementia with pallidopontonigral degeneration (PPND) (Wszolek et al., 1992); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (Lynch et al., 1994); frontotemporal dementia with parkinsonism (FLDEM) (Yamaoka et al., 1996); and multiple system tauopathy with presenile dementia (MSTD) (Spillantini et al., 1997). These disorders are characterized by variable degrees of frontal lobe dementia, parkinsonism, motor neuron disease, and amyotrophy. Other neurodegenerative associated with mutations in the MAPT gene include Pick disease (172700) and progressive supranuclear palsy (PSP; 601104), Inherited neurodegenerative tauopathies linked to chromosome 17 and caused by mutation in the MAPT gene have also been collectively termed 'FTDP17' (Lee et al., 2001). Kertesz (2003) suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), PSP, and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies. Genetic Heterogeneity of Frontotemporal Lobar Degeneration Mutations in several different genes can cause frontotemporal dementia and frontotemporal lobar degeneration, with or without motor neuron disease. See FTLD with TDP43 inclusions (607485), caused by mutation in the GRN gene (138945) on chromosome 17q21; FTLD mapping to chromosome 3 (600795), caused by mutation in the CHMP2B gene (609512); inclusion body myopathy with Paget disease and FTD (IBMPFD; 167320), caused by mutation in the VCP gene (601023) on chromosome 9p13; ALS6 (608030), caused by mutation in the FUS gene (137070) on 16p11; ALS10 (612069), caused by mutation in the TARDBP gene (605078) on 1p36; and FTDALS (105550), caused by mutation in the C9ORF72 gene (614260) on 9p. In 1 family with FTD, a mutation was identified in the presenilin-1 gene (PSEN1; 104311) on chromosome 14, which is usually associated with a familial form of early-onset Alzheimer disease (AD3; 607822).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:87254053
Likely benign
Hetero
Gene:
KCNQ1
Variant:
c.*264T>C
rsID: rs45579540
Ref Allele: T
Alt Allele: C
Freq: 1.056%uncommon
CADD: 0.562
ClinVar Submissions (1)
Familial atrial fibrillation is an inherited abnormality of the heart's normal rhythm. Atrial fibrillation is characterized by episodes of uncoordinated electrical activity (fibrillation) in the heart's upper chambers (the atria), which cause a fast and irregular heartbeat. If untreated, this abnormal heart rhythm (arrhythmia) can lead to dizziness, chest pain, a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, or fainting (syncope). Atrial fibrillation also increases the risk of stroke and sudden death. Complications of atrial fibrillation can occur at any age, although some people with this heart condition never experience any health problems associated with the disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:2848267
Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec. Prolongation of the QTc interval is associated with tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation, which may culminate in syncope or sudden death. Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS. The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. Fifty percent of individuals with JLNS had cardiac events before age three years. More than half of untreated children with JLNS die before age 15 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:2848267
A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:2848267
Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the ECG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7), hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8), and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:2848267
Short QT syndrome is a condition that can cause a disruption of the heart's normal rhythm (arrhythmia). In people with this condition, the heart (cardiac) muscle takes less time than usual to recharge between beats. The term "short QT" refers to a specific pattern of heart activity that is detected with an electrocardiogram (EKG), which is a test used to measure the electrical activity of the heart. In people with this condition, the part of the heartbeat known as the QT interval is abnormally short.If untreated, the arrhythmia associated with short QT syndrome can lead to a variety of signs and symptoms, from dizziness and fainting (syncope) to cardiac arrest and sudden death. These signs and symptoms can occur any time from early infancy to old age. This condition may explain some cases of sudden infant death syndrome (SIDS), which is a major cause of unexplained death in babies younger than 1 year. However, some people with short QT syndrome never experience any health problems associated with the condition.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:2848267
Likely benign
Hetero
Gene:
MUTYH
Variant:
c.1544C>T
(p.Ser515Phe)
rsID: rs140118273
Ref Allele: G
Alt Allele: A
Freq: 1.0759%uncommon
CADD: 17.51
ClinVar Submissions (15)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Feb 20, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 15
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:45329412
MUTYH-associated polyposis (MAP), caused by biallelic pathogenic variants in MUTYH, is characterized by a greatly increased lifetime risk of colorectal cancer (CRC) (43% to almost 100% in the absence of timely surveillance). Although typically associated with ten to a few hundred colonic adenomatous polyps that are evident at a mean age of about 50 years, colonic cancer develops in some individuals with biallelic MUTYH pathogenic variants in the absence of polyposis. Duodenal adenomas are found in 17%-25% of individuals with MAP. Serrated adenomas, hyperplastic/sessile serrated polyps, and mixed (hyperplastic and adenomatous) polyps can also occur. The lifetime risk of duodenal cancer is about 4%. Also noted are a modestly increased risk for rather late-onset malignancies of the ovary, bladder, and skin, and some evidence for an increased risk for breast and endometrial cancer. Some affected individuals develop sebaceous gland tumors and more recently, thyroid abnormalities (multinodular goiter, single nodules, and papillary thyroid cancer) have been reported.
Last Evaluated: Feb 20, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 15
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:45329412
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 20, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 15
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:45329412
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 20, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 15
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:45329412
Benign/Likely benign
Hetero
Gene:
MYH3
Variant:
c.3009G>A
(p.Ala1003=)
rsID: rs61735353
Ref Allele: C
Alt Allele: T
Freq: 1.0759%uncommon
CADD: 10.36
ClinVar Submissions (3)
A non-progressive finding characterized by multiple joint contractures found throughout the body at birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10639391
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10639391
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10639391
Benign/Likely benign
Hetero
Gene:
PRDM1
Variant:
c.1061G>A
(p.Ser354Asn)
rsID: rs143040512
Ref Allele: G
Alt Allele: A
Freq: 1.0815%uncommon
CADD: 22.7
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 19, 2013
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 6:106105221
Hetero
Gene:
SMARCA4
Variant:
c.1114T>C
(p.Tyr372His)
rsID: rs140192268
Ref Allele: T
Alt Allele: C
Freq: 1.0815%uncommon
CADD: 22.1
ClinVar Submissions (7)
Coffin-Siris syndrome is a multiple malformation syndrome characterized by mental retardation associated with coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. Other more variable features may include poor overall growth, craniofacial abnormalities, spinal anomalies, and congenital heart defects (review by Vergano and Deardorff, 2014). Mutations in the ARID1B gene are the most common cause of Coffin-Siris syndrome (Wieczorek et al., 2013). Genetic Heterogeneity of Coffin-Siris Syndrome Forms of Coffin-Siris syndrome have been shown to be caused by mutations in genes encoding subunits of the SWI/SNF complex, also known as the BAF complex, which functions as a chromatin remodeling factor. These include CSS2 (614607), caused by mutation in the ARID1A gene (603024); CSS3 (614608), caused by mutation in the SMARCB1 gene (601607); CSS4 (614609), caused by mutation in the SMARCA4 gene (603254); CSS5 (616938), caused by mutation in the SMARCE1 gene (603111); CSS6 (617808), caused by mutation in the ARID2 gene (609539); and CSS7 (618027), caused by mutation in the DPF2 gene (601671). A similar phenotype, Nicolaides-Baraitser syndrome (NCBRS; 601358), is also caused by mutation in a subunit of this complex, i.e., SMARCA2 (600014).
Last Evaluated: Jan 15, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:10987920
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Jan 15, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:10987920
Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk of developing rhabdoid tumors – rare and highly aggressive malignant tumors occurring predominantly in infants and children younger than age three years. Rhabdoid tumors can occur in almost any anatomic location, commonly in the central nervous system (i.e., atypical teratoid/rhabdoid tumor [AT/RT]); more than 50% occur in the cerebellum. Other common locations include extracranial extrarenal malignant rhabdoid tumors (e.g., rhabdoid tumors of the head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart) (eMRT), rhabdoid tumor of the kidney (RTK), and possibly small-cell carcinoma of the ovary (hypercalcemic type). Individuals with RTPS typically present before age 12 months with synchronous tumors that exhibit aggressive clinical behavior.
Last Evaluated: Jan 15, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:10987920
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 15, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:10987920
Benign/Likely benign
Hetero
Gene:
ARL6
Variant:
c.*284C>A
rsID: rs148380165
Ref Allele: C
Alt Allele: A
Freq: 1.0903%uncommon
CADD: 1.729
ClinVar Submissions (1)
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:97798333
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:97798333
Conflicting/Uncertain
Hetero
Gene:
BBS9
Variant:
c.2299-20A>C
rsID: rs17727583
Ref Allele: A
Alt Allele: C
Freq: 1.107%uncommon
CADD: 4.322
ClinVar Submissions (5)
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Last Evaluated: May 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:33533934
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:33533934
Benign
Hetero
Gene:
CERKL
Variant:
c.*295G>A
rsID: rs148226735
Ref Allele: C
Alt Allele: T
Freq: 1.1118%uncommon
CADD: 6.787
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:181537889
Conflicting/Uncertain
Hetero
Gene:
VLDLR
Variant:
c.-113C>G
rsID: rs34433332
Ref Allele: C
Alt Allele: G
Freq: 1.1173%uncommon
CADD: 14.82
ClinVar Submissions (1)
Hypoplasia of the cerebellum that is associated with inherited metabolic disorders and neurodegenerative disorders. Signs and symptoms include mental and developmental delays, walking and balance difficulties, floppy muscle tone, and seizures.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:2622077
Conflicting/Uncertain
Hetero
Gene:
KCNA1
Variant:
c.*1522C>G
rsID: rs140297443
Ref Allele: C
Alt Allele: G
Freq: 1.1261%uncommon
CADD: 16.8
ClinVar Submissions (1)
Periodic spells of incoordination and imbalance, that is, episodes of ataxia typically lasting from 10 minutes to several hours or days.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:4914388
A disorder characterized by involuntary and irregular muscle contractions not associated with muscle weakness or atrophy. It most often affects facial muscles. It may be localized or generalized.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:4914388
Likely benign
Hetero
Gene:
ABCB7
Variant:
c.249+1G>A
rsID: rs61323727
Ref Allele: C
Alt Allele: T
Freq: 1.1516%uncommon
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: X:75114753
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: X:75114753
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: X:75114753
Conflicting/Uncertain
Hetero
Gene:
FHL1
Variant:
c.823G>A
(p.Asp275Asn)
rsID: rs151315725
Ref Allele: G
Alt Allele: A
Freq: 1.1556%uncommon
ClinVar Submissions (3)
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures that begin in early childhood, slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles, and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:136210005
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:136210005
Benign
Hetero
Gene:
DHCR24
Variant:
c.180C>T
(p.Leu60=)
rsID: rs79857573
Ref Allele: G
Alt Allele: A
Freq: 1.1564%uncommon
CADD: 18.16
ClinVar Submissions (1)
Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells (summary by Waterham et al., 2001).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:54886940
Conflicting/Uncertain
Hetero
Gene:
IL17RC
Variant:
c.853G>A
(p.Val285Met)
rsID: rs75692599
Ref Allele: G
Alt Allele: A
Freq: 1.1579%uncommon
CADD: 23
ClinVar Submissions (1)
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:9923898
Benign
Hetero
Gene:
GLIS3
Variant:
c.1071C>A
(p.Asp357Glu)
rsID: rs148199056
Ref Allele: G
Alt Allele: T
Freq: 1.1603%uncommon
CADD: 19.87
ClinVar Submissions (3)
Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome is characterized by intrauterine growth retardation and onset of nonimmune diabetes mellitus within the first few weeks of life. Other features include renal parenchymal disease, primarily renal cystic dysplasia, and hepatic disease, with hepatitis in some patients and hepatic fibrosis and cirrhosis in others. Facial dysmorphism, when present, consistently involves low-set ears, epicanthal folds, flat nasal bridge, long philtrum, and thin upper lip. Most patients exhibit developmental delay (Dimitri et al., 2015).
Last Evaluated: Oct 18, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:4117942
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 18, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:4117942
Benign/Likely benign
Hetero
Gene:
PIEZO1
Variant:
c.6963C>T
(p.Asn2321=)
rsID: rs35917730
Ref Allele: G
Alt Allele: A
Freq: 1.181%uncommon
CADD: 1.449
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 18, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:88716447
Benign
Hetero
Gene:
CHRNA2
Variant:
c.771C>T
(p.Tyr257=)
rsID: rs56229264
Ref Allele: G
Alt Allele: A
Freq: 1.2129%uncommon
CADD: 16.17
ClinVar Submissions (4)
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidity, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:27463672
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:27463672
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:27463672
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:27463672
Benign/Likely benign
Hetero
Gene:
MYLK
Variant:
c.1327C>T
(p.Pro443Ser)
rsID: rs35156360
Ref Allele: G
Alt Allele: A
Freq: 1.2225%uncommon
CADD: 26.2
ClinVar Submissions (8)
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123733085
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123733085
Familial thoracic aortic aneurysm and dissection (familial TAAD) involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax). Other vessels that carry blood from the heart to the rest of the body (arteries) can also be affected.In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), which can lead to a bulge in the blood vessel wall (an aneurysm). Aortic dilatation may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers. These aortic abnormalities are potentially life-threatening because they can decrease blood flow to other parts of the body such as the brain or other vital organs, or cause the aorta to break open (rupture).The occurrence and timing of these aortic abnormalities vary, even within the same affected family. They can begin in childhood or not occur until late in life. Aortic dilatation is generally the first feature of familial TAAD to develop, although in some affected individuals dissection occurs with little or no aortic dilatation.Aortic aneurysms usually have no symptoms. However, depending on the size, growth rate, and location of these abnormalities, they can cause pain in the jaw, neck, chest, or back; swelling in the arms, neck, or head; difficult or painful swallowing; hoarseness; shortness of breath; wheezing; a chronic cough; or coughing up blood. Aortic dissections usually cause severe, sudden chest or back pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias) in one or more limbs, or paralysis.Familial TAAD may not be associated with other signs and symptoms. However, some individuals in affected families show mild features of related conditions called Marfan syndrome or Loeys-Dietz syndrome. These features include tall stature, stretch marks on the skin, an unusually large range of joint movement (joint hypermobility), and either a sunken or protruding chest. Occasionally, people with familial TAAD develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have heart abnormalities that are present from birth (congenital). Affected individuals may also have a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries). However, these conditions are also common in the general population. Depending on the genetic cause of familial TAAD in particular families, they may have an increased risk of developing blockages in smaller arteries, which can lead to heart attack and stroke.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123733085
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123733085
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123733085
Benign/Likely benign
Hetero
Gene:
ABCA1
Variant:
c.4536G>T
(p.Thr1512=)
rsID: rs41277763
Ref Allele: C
Alt Allele: A
Freq: 1.2272%uncommon
CADD: 3.057
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:104804649
Tangier disease is an autosomal recessive disorder characterized by markedly reduced levels of plasma high density lipoproteins (HDL) resulting in tissue accumulation of cholesterol esters. Clinical features include very large, yellow-orange tonsils, enlarged liver, spleen and lymph nodes, hypocholesterolemia, and abnormal chylomicron remnants (Brooks-Wilson et al., 1999).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:104804649
Likely benign
Hetero
Gene:
ERCC8
Variant:
c.*237T>C
rsID: rs4647153
Ref Allele: A
Alt Allele: G
Freq: 1.2296%uncommon
CADD: 1.694
ClinVar Submissions (1)
Cockayne syndrome (referred to as CS in this GeneReview) spans a phenotypic spectrum that includes: CS type I, the "classic" or "moderate" form; CS type II, a more severe form with symptoms present at birth; this form overlaps with cerebrooculofacioskeletal syndrome (COFS) or Pena-Shokeir syndrome type II; CS type III, a milder form; Xeroderma pigmentosum-Cockayne syndrome (XP-CS). CS type I (moderate CS) is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade. CS type II (severe CS or early-onset CS) is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age seven years. CS type III (mild CS or late-onset CS) is characterized by essentially normal growth and cognitive development or by late onset. Xeroderma pigmentosum-Cockayne syndrome (XP-CS) includes facial freckling and early skin cancers typical of XP and some features typical of CS, including intellectual disability, spasticity, short stature, and hypogonadism. XP-CS does not include skeletal involvement, the facial phenotype of CS, or CNS dysmyelination and calcifications.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:60874378
Likely benign
Hetero
Gene:
ABCG8
Variant:
c.165+13C>T
rsID: rs75365565
Ref Allele: C
Alt Allele: T
Freq: 1.2328%uncommon
CADD: 4.765
ClinVar Submissions (1)
Sitosterolemia is characterized by: Tendon xanthomas or tuberous (i.e., planar) xanthomas that can occur in childhood and in unusual locations (heels, knees, elbows and buttocks); Premature atherosclerosis which can lead to angina, aortic valve involvement, myocardial infarction, and sudden death; Hemolytic anemia, abnormally shaped erythrocytes (stomatocytes), and large platelets (macrothrombocytopenia). On occasion, the abnormal hematologic findings may be the initial presentation. The phenotypic spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis and the fact that clinical findings in infants are likely to be highly dependent on diet.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:43844621
Likely benign
Hetero
Gene:
APC
Variant:
c.1744-363T>A
rsID: rs77504726
Ref Allele: T
Alt Allele: A
Freq: 1.2599%uncommon
CADD: 2.64
ClinVar Submissions (1)
Colorectal cancer is a heterogeneous disease that is common in both men and women. In addition to lifestyle and environmental risk factors, gene defects can contribute to an inherited predisposition to CRC. CRC is caused by changes in different molecular pathogenic pathways, such as chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Chromosome instability is the most common alteration and is present in almost 85% of all cases (review by Schweiger et al., 2013). Genetic Heterogeneity of Colorectal Cancer Mutations in a single gene result in a marked predisposition to colorectal cancer in 2 distinct syndromes: familial adenomatous polyposis (FAP; 175100) and hereditary nonpolyposis colorectal cancer (HNPCC; see 120435). FAP is caused by mutations in the APC gene (611731), whereas HNPCC is caused by mutations in several genes, including MSH2 (609309), MLH1 (120436), PMS1 (600258), PMS2 (600259), MSH6 (600678), TGFBR2 (190182), and MLH3 (604395). Epigenetic silencing of MSH2 results in a form of HNPCC (see HNPCC8, 613244). Other colorectal cancer syndromes include autosomal recessive adenomatous polyposis (608456), which is caused by mutations in the MUTYH gene (604933), and oligodontia-colorectal cancer syndrome (608615), which is caused by mutations in the AXIN2 gene (604025). The CHEK2 gene (604373) has been implicated in susceptibility to colorectal cancer in Finnish patients. A germline mutation in the PLA2G2A gene (172411) was identified in a patient with colorectal cancer. Germline susceptibility loci for colorectal cancer have also been identified. CRCS1 (608812) is conferred by mutation in the GALNT12 gene (610290) on chromosome 9q22; CRCS2 (611469) maps to chromosome 8q24; CRCS3 (612229) is conferred by variation in the SMAD7 gene (602932) on chromosome 18; CRCS4 (601228) is conferred by variation on 15q that causes increased and ectopic expression of the GREM1 gene (603054); CRCS5 (612230) maps to chromosome 10p14; CRCS6 (612231) maps to chromosome 8q23; CRCS7 (612232) maps to chromosome 11q23; CRCS8 (612589) maps to chromosome 14q22; CRCS9 (612590) maps to 16q22; CRCS10 (612591) is conferred by mutation in the POLD1 gene (174761) on chromosome 19q13; CRCS11 (612592) maps to chromosome 20p12; and CRCS12 (615083) is conferred by mutation in the POLE gene (174762) on chromosome 12q24. Somatic mutations in many different genes, including KRAS (190070), PIK3CA (171834), BRAF (164757), CTNNB1 (116806), FGFR3 (134934), AXIN2 (604025), AKT1 (164730), MCC (159350), MYH11 (160745), PARK2 (602544), and RNF43 (612482), have been identified in colorectal cancer.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: other
Assembly: GRCh38
Chromosome/Position: 5:112834588
Hetero
Gene:
PDSS2
Variant:
c.7T>C
(p.Phe3Leu)
rsID: rs3734675
Ref Allele: A
Alt Allele: G
Freq: 1.2647%uncommon
CADD: 21.2
ClinVar Submissions (4)
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:107459279
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:107459279
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:107459279
Benign/Likely benign
Hetero
Gene:
PDSS2
Variant:
c.11G>C
(p.Arg4Pro)
rsID: rs3734676
Ref Allele: C
Alt Allele: G
Freq: 1.2655%uncommon
CADD: 18.05
ClinVar Submissions (4)
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:107459275
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:107459275
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:107459275
Benign/Likely benign
Hetero
Gene:
PRICKLE2
Variant:
c.-68G>A
rsID: rs150393747
Ref Allele: C
Alt Allele: T
Freq: 1.271%uncommon
CADD: 0.83
ClinVar Submissions (1)
A heterogeneous group of primarily familial EPILEPSY disorders characterized by myoclonic seizures, tonic-clonic seizures, ataxia, progressive intellectual deterioration, and neuronal degeneration. These include LAFORA DISEASE; MERRF SYNDROME; NEURONAL CEROID-LIPOFUSCINOSIS; sialidosis (see MUCOLIPIDOSES), and UNVERRICHT-LUNDBORG SYNDROME.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:64224937
Likely benign
Hetero
Gene:
NRAS
Variant:
c.*416A>C
rsID: rs9724643
Ref Allele: T
Alt Allele: G
Freq: 1.2742%uncommon
CADD: 17
ClinVar Submissions (1)
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:114707678
Likely benign
Hetero
Gene:
TTN
Variant:
c.58910G>A
(p.Arg19637Lys)
rsID: rs72646869
Ref Allele: C
Alt Allele: T
Freq: 1.2838%uncommon
CADD: 22.4
ClinVar Submissions (7)
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178581654
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178581654
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178581654
Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, Udd distal myopathy can remain unnoticed even in the elderly.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178581654
Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support. The disease course varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178581654
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178581654
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178581654
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178581654
Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between age 20 months and four years. In the first decade of life, global motor performances are stable or tend to improve. Moderate joint and neck contractures and spinal rigidity may start in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction starts between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178581654
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178581654
Conflicting/Uncertain
Hetero
Gene:
LPIN2
Variant:
c.*1502G>A
rsID: rs113346639
Ref Allele: C
Alt Allele: T
Freq: 1.2846%uncommon
CADD: 1.265
ClinVar Submissions (1)
Majeed syndrome is characterized by: Chronic recurrent multifocal osteomyelitis (CRMO) that is of early onset with a lifelong course; and Congenital dyserythropoietic anemia (CDA) that presents as hypochromic, microcytic anemia during the first year of life and ranges from mild to transfusion dependent. Some individuals also develop a transient inflammatory dermatosis, often manifesting as Sweet syndrome (neutrophilic skin infiltration).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 18:2918791
Conflicting/Uncertain
Hetero
Gene:
PRICKLE2
Variant:
c.-252G>C
rsID: rs142388795
Ref Allele: C
Alt Allele: G
Freq: 1.2957%uncommon
CADD: 7.966
ClinVar Submissions (1)
A heterogeneous group of primarily familial EPILEPSY disorders characterized by myoclonic seizures, tonic-clonic seizures, ataxia, progressive intellectual deterioration, and neuronal degeneration. These include LAFORA DISEASE; MERRF SYNDROME; NEURONAL CEROID-LIPOFUSCINOSIS; sialidosis (see MUCOLIPIDOSES), and UNVERRICHT-LUNDBORG SYNDROME.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:64225121
Likely benign
Hetero
Gene:
FAT4
Variant:
c.14129C>G
(p.Ser4710Cys)
rsID: rs147662558
Ref Allele: C
Alt Allele: G
Freq: 1.3045%uncommon
CADD: 23.6
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 22, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:125490951
Benign
Hetero
Gene:
HOGA1
Variant:
c.834+42G>T
rsID: rs115279832
Ref Allele: G
Alt Allele: T
Freq: 1.3085%uncommon
CADD: 0.747
ClinVar Submissions (1)
Primary hyperoxaluria is a rare condition characterized by recurrent kidney and bladder stones. The condition often results in end stage renal disease (ESRD), which is a life-threatening condition that prevents the kidneys from filtering fluids and waste products from the body effectively.Primary hyperoxaluria results from the overproduction of a substance called oxalate. Oxalate is filtered through the kidneys and excreted as a waste product in urine, leading to abnormally high levels of this substance in urine (hyperoxaluria). During its excretion, oxalate can combine with calcium to form calcium oxalate, a hard compound that is the main component of kidney and bladder stones. Deposits of calcium oxalate can damage the kidneys and other organs and lead to blood in the urine (hematuria), urinary tract infections, kidney damage, ESRD, and injury to other organs. Over time, kidney function decreases such that the kidneys can no longer excrete as much oxalate as they receive. As a result oxalate levels in the blood rise, and the substance gets deposited in tissues throughout the body (systemic oxalosis), particularly in bones and the walls of blood vessels. Oxalosis in bones can cause fractures.There are three types of primary hyperoxaluria that differ in their severity and genetic cause. In primary hyperoxaluria type 1, kidney stones typically begin to appear anytime from childhood to early adulthood, and ESRD can develop at any age. Primary hyperoxaluria type 2 is similar to type 1, but ESRD develops later in life. In primary hyperoxaluria type 3, affected individuals often develop kidney stones in early childhood, but few cases of this type have been described so additional signs and symptoms of this type are unclear.
Last Evaluated: Nov 27, 2014
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:97602032
Conflicting/Uncertain
Hetero
Gene:
RTEL1
Variant:
c.3173C>A
(p.Pro1058His)
rsID: rs115610405
Ref Allele: C
Alt Allele: A
Freq: 1.3164%uncommon
CADD: 14.19
ClinVar Submissions (1)
Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. The classic triad may not be present in all individuals. People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include: abnormal pigmentation changes not restricted to the upper chest and neck, eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), and dental abnormalities (caries, periodontal disease, taurodauntism). Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the two variants in which additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome). Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 20:63694480
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 20:63694480
Benign
Hetero
Gene:
CDC6
Variant:
c.883G>A
(p.Asp295Asn)
rsID: rs4135012
Ref Allele: G
Alt Allele: A
Freq: 1.3427%uncommon
CADD: 27.7
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 21, 2013
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:40293996
Benign
Hetero
Gene:
SCN3A
Variant:
c.5584G>T
(p.Gly1862Cys)
rsID: rs41265137
Ref Allele: C
Alt Allele: A
Freq: 1.3634%uncommon
CADD: 27.7
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 23, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:165090569
Benign
Hetero
Gene:
ANKRD26
Variant:
c.3384G>A
(p.Lys1128=)
rsID: rs41299210
Ref Allele: C
Alt Allele: T
Freq: 1.4152%uncommon
CADD: 15.21
ClinVar Submissions (2)
A reduction in the number of circulating thrombocytes.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:27035066
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:27035066
Benign/Likely benign
Hetero
Gene:
ANO6
Variant:
c.1783-13T>C
rsID: rs117316516
Ref Allele: T
Alt Allele: C
Freq: 1.4239%uncommon
CADD: 17.64
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:45403426
Benign
Hetero
Gene:
TMC3
Variant:
c.3134C>A
(p.Ser1045Ter)
rsID: rs150843673
Ref Allele: G
Alt Allele: T
Freq: 1.443%uncommon
CADD: 44
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 06, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:81332588
Benign
Hetero
Gene:
SMPD1
Variant:
c.1749G>A
(p.Ser583=)
rsID: rs35098198
Ref Allele: G
Alt Allele: A
Freq: 1.4438%uncommon
CADD: 1.733
ClinVar Submissions (3)
Acid sphingomyelinase (ASM) deficiency has been categorized in the past as either neuronopathic (Niemann-Pick disease type A [NPD-A]), with death in early childhood, or non-neuronopathic (Niemann-Pick disease type B [NPD-B]). While forms intermediate to these two extremes occur, all ASM deficiency that is not NPD-A is designated in this review as NPD-B, despite its wide range of manifestations and severity. The first symptom in NPD-A is hepatosplenomegaly, usually noted by age three months; over time the liver and spleen become massive. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most children succumb before the third year. NPD type B, later in onset and milder in manifestations than NPD type A, is characterized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary function, osteopenia, and atherogenic lipid profile. Progressive and/or clinically significant neurologic manifestations occur infrequently. Survival to adulthood can occur.
Last Evaluated: May 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:6394460
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:6394460
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:6394460
Conflicting/Uncertain
Hetero
Gene:
LOXHD1
Variant:
c.1894G>T
(p.Gly632Cys)
rsID: rs35088381
Ref Allele: C
Alt Allele: A
Freq: 1.4773%uncommon
CADD: 26.6
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:46577783
Benign
Homo
Gene:
LOXHD1
Variant:
c.1876G>T
(p.Gly626Cys)
rsID: rs34589386
Ref Allele: C
Alt Allele: A
Freq: 1.4773%uncommon
CADD: 27.8
ClinVar Submissions (3)
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:46577801
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:46577801
Conflicting/Uncertain
Homo
Gene:
CTSA
Variant:
c.-223G>A
rsID: rs117529875
Ref Allele: G
Alt Allele: A
Freq: 1.4853%uncommon
CADD: 5.961
ClinVar Submissions (1)
Galactosialidosis is a lysosomal storage disease associated with a combined deficiency of beta-galactosidase (611458) and neuraminidase (608272), secondary to a defect in protective protein/cathepsin A (PPCA). All patients have clinical manifestations typical of a lysosomal disorder, such as coarse facies, cherry red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes. Three phenotypic subtypes are recognized. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile type is characterized by hepatosplenomegaly, growth retardation, cardiac involvement, and rare occurrence of neurologic signs. The juvenile/adult form is characterized by myoclonus, ataxia, angiokeratoma, mental retardation, neurologic deterioration, absence of visceromegaly, and long survival. The majority of reported patients belong to the juvenile/adult group and are mainly of Japanese origin (summary by d'Azzo et al., 2001).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 20:45891103
Likely benign
Hetero
Gene:
MITF
Variant:
c.-36G>A
rsID: rs77588960
Ref Allele: G
Alt Allele: A
Freq: 1.4868%uncommon
CADD: 0.03
ClinVar Submissions (2)
Tietz syndrome is a disorder characterized by profound hearing loss from birth, fair skin, and light-colored hair. The hearing loss in affected individuals is caused by abnormalities of the inner ear (sensorineural hearing loss) and is present from birth. Although people with Tietz syndrome are born with white hair and very pale skin, their hair color often darkens over time to blond or red. The skin of affected individuals, which sunburns very easily, may tan slightly or develop reddish freckles with limited sun exposure; however, their skin and hair color remain lighter than those of other members of their family.Tietz syndrome also affects the eyes. The colored part of the eye (the iris) in affected individuals is blue, and specialized cells in the eye called retinal pigment epithelial cells lack their normal pigment. The retinal pigment epithelium nourishes the retina, the part of the eye that detects light and color. The changes to the retinal pigment epithelium are generally detectable only by an eye examination; it is unclear whether the changes affect vision.
Last Evaluated: Oct 19, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:69936687
A rare, autosomal dominant inherited syndrome caused by mutations in the PAX3, MITF, and SNAI2 genes. Signs and symptoms include hearing loss, dystopia canthorum (widely spaced inner corners of the eyes), and changes in the color of the skin, hair, and eyes.
Last Evaluated: Oct 19, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:69936687
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 19, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:69936687
Benign/Likely benign
Hetero
Gene:
SMARCAL1
Variant:
c.1947C>T
(p.Asp649=)
rsID: rs2066526
Ref Allele: C
Alt Allele: T
Freq: 1.4948%uncommon
CADD: 0.686
ClinVar Submissions (3)
Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small deformed capital femoral epiphyses, and shallow dysplastic acetabular fossae. Adult height is 136-157 cm for men and 98.5-143 cm for women. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease (ESRD). The majority of tested individuals have T-cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with death early in life to a juvenile or milder later-onset form with survival into adulthood if renal disease is appropriately treated.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:216450941
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:216450941
Benign/Likely benign
Hetero
Gene:
MITF
Variant:
c.*2458G>A
rsID: rs77962238
Ref Allele: G
Alt Allele: A
Freq: 1.4988%uncommon
CADD: 14.05
ClinVar Submissions (1)
Tietz syndrome is a disorder characterized by profound hearing loss from birth, fair skin, and light-colored hair. The hearing loss in affected individuals is caused by abnormalities of the inner ear (sensorineural hearing loss) and is present from birth. Although people with Tietz syndrome are born with white hair and very pale skin, their hair color often darkens over time to blond or red. The skin of affected individuals, which sunburns very easily, may tan slightly or develop reddish freckles with limited sun exposure; however, their skin and hair color remain lighter than those of other members of their family.Tietz syndrome also affects the eyes. The colored part of the eye (the iris) in affected individuals is blue, and specialized cells in the eye called retinal pigment epithelial cells lack their normal pigment. The retinal pigment epithelium nourishes the retina, the part of the eye that detects light and color. The changes to the retinal pigment epithelium are generally detectable only by an eye examination; it is unclear whether the changes affect vision.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:69967706
A rare, autosomal dominant inherited syndrome caused by mutations in the PAX3, MITF, and SNAI2 genes. Signs and symptoms include hearing loss, dystopia canthorum (widely spaced inner corners of the eyes), and changes in the color of the skin, hair, and eyes.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:69967706
Likely benign
Hetero
Gene:
TSHR
Variant:
c.1377G>A
(p.Ala459=)
rsID: rs113951800
Ref Allele: G
Alt Allele: A
Freq: 1.5036%uncommon
CADD: 3.347
ClinVar Submissions (2)
Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.Signs and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.Congenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:81143435
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:81143435
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:81143435
Benign/Likely benign
Hetero
Gene:
SZT2
Variant:
c.2929+9G>A
rsID: rs114863461
Ref Allele: G
Alt Allele: A
Freq: 1.5107%uncommon
CADD: 10.54
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:43425958
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:43425958
Benign
Hetero
Gene:
DNAH1
Variant:
c.7569C>T
(p.Ser2523=)
rsID: rs73072968
Ref Allele: C
Alt Allele: T
Freq: 1.5107%uncommon
CADD: 2.328
ClinVar Submissions (1)
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:52380096
Spermatogenic failure-18 is a form of male infertility caused by multiple morphologic abnormalities of the sperm flagella (Ben Khelifa et al., 2014). For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:52380096
Benign
Hetero
Gene:
MITF
Variant:
c.*1150T>C
rsID: rs150314710
Ref Allele: T
Alt Allele: C
Freq: 1.5179%uncommon
CADD: 11.21
ClinVar Submissions (1)
Tietz syndrome is a disorder characterized by profound hearing loss from birth, fair skin, and light-colored hair. The hearing loss in affected individuals is caused by abnormalities of the inner ear (sensorineural hearing loss) and is present from birth. Although people with Tietz syndrome are born with white hair and very pale skin, their hair color often darkens over time to blond or red. The skin of affected individuals, which sunburns very easily, may tan slightly or develop reddish freckles with limited sun exposure; however, their skin and hair color remain lighter than those of other members of their family.Tietz syndrome also affects the eyes. The colored part of the eye (the iris) in affected individuals is blue, and specialized cells in the eye called retinal pigment epithelial cells lack their normal pigment. The retinal pigment epithelium nourishes the retina, the part of the eye that detects light and color. The changes to the retinal pigment epithelium are generally detectable only by an eye examination; it is unclear whether the changes affect vision.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:69966398
A rare, autosomal dominant inherited syndrome caused by mutations in the PAX3, MITF, and SNAI2 genes. Signs and symptoms include hearing loss, dystopia canthorum (widely spaced inner corners of the eyes), and changes in the color of the skin, hair, and eyes.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:69966398
Likely benign
Hetero
Gene:
CRYBA4
Variant:
c.106G>A
(p.Val36Met)
rsID: rs35520672
Ref Allele: G
Alt Allele: A
Freq: 1.5179%uncommon
CADD: 23.7
ClinVar Submissions (2)
Microphthalmia, anophthalmia, and coloboma comprise the MAC spectrum of ocular malformations. Microphthalmia refers to a globe with a total axial length that is at least two standard deviations below the mean for age. Anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Coloboma refers to the ocular malformations that result from failure of closure of the optic fissure. Chorioretinal coloboma refers to coloboma of the retina and choroid. Iris coloboma causes the iris to appear keyhole-shaped. Microphthalmia, anophthalmia, and coloboma may be unilateral or bilateral; when bilateral they may occur in any combination.
Last Evaluated: May 23, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:26623300
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 23, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:26623300
Benign
Hetero
Gene:
GLRA1
Variant:
c.1041G>A
(p.Arg347=)
rsID: rs75463357
Ref Allele: C
Alt Allele: T
Freq: 1.5386%uncommon
CADD: 8.595
ClinVar Submissions (2)
Hereditary hyperekplexia (HPX) is characterized by generalized stiffness immediately after birth that normalizes during the first years of life; excessive startle reflex (eye blinking and a flexor spasm of the trunk) to unexpected (particularly auditory) stimuli; and a short period of generalized stiffness following the startle response during which voluntary movements are impossible. Exaggerated head-retraction reflex (HRR) consisting of extension of the head followed by violent flexor spasms of limbs and neck muscles elicited by tapping the tip of the nose is observed in most children. Other findings include periodic limb movements in sleep (PLMS) and hypnagogic (occurring when falling asleep) myoclonus. Sudden infant death (SIDS) has been reported. Intellect is usually normal; mild intellectual disability may occur.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:151828939
Hereditary hyperekplexia (HPX) is characterized by generalized stiffness immediately after birth that normalizes during the first years of life; excessive startle reflex (eye blinking and a flexor spasm of the trunk) to unexpected (particularly auditory) stimuli; and a short period of generalized stiffness following the startle response during which voluntary movements are impossible. Exaggerated head-retraction reflex (HRR) consisting of extension of the head followed by violent flexor spasms of limbs and neck muscles elicited by tapping the tip of the nose is observed in most children. Other findings include periodic limb movements in sleep (PLMS) and hypnagogic (occurring when falling asleep) myoclonus. Sudden infant death (SIDS) has been reported. Intellect is usually normal; mild intellectual disability may occur.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:151828939
Benign/Likely benign
Hetero
Gene:
INF2
Variant:
c.391+17G>A
rsID: rs4074531
Ref Allele: G
Alt Allele: A
Freq: 1.541%uncommon
CADD: 0.756
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 06, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:104701773
Benign
Hetero
Gene:
GABRD
Variant:
c.659G>A
(p.Arg220His)
rsID: rs41307846
Ref Allele: G
Alt Allele: A
Freq: 1.5649%uncommon
CADD: 22.1
ClinVar Submissions (3)
Idiopathic generalized epilepsy (EIG) is a broad term that encompasses several common seizure phenotypes, classically including childhood absence epilepsy (CAE, ECA), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME, EJM) (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Generalized epilepsy with febrile seizures plus (GEFS+) shows phenotypic overlap with IGE, and includes patients with early-onset febrile seizures who later develop various types of febrile and afebrile seizures, such as those observed in EIG (summary by Singh et al., 1999). For a general phenotypic description and a discussion of genetic heterogeneity of EIG, see 600669. For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233. For a general phenotypic description and a discussion of genetic heterogeneity of EJM, see 254770.
Last Evaluated: Jun 29, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign, risk factor
Assembly: GRCh38
Chromosome/Position: 1:2028260
OMIM Allelic Variant: 137163.0002
Last Evaluated: Jun 29, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign, risk factor
Assembly: GRCh38
Chromosome/Position: 1:2028260
OMIM Allelic Variant: 137163.0002
Last Evaluated: Jun 29, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign, risk factor
Assembly: GRCh38
Chromosome/Position: 1:2028260
OMIM Allelic Variant: 137163.0002
Idiopathic generalized epilepsy is a broad term that encompasses several common seizure phenotypes, classically including childhood absence epilepsy (CAE, ECA; see 600131), juvenile absence epilepsy (JAE, EJA; see 607631), juvenile myoclonic epilepsy (JME, EJM; see 254770), and epilepsy with grand mal seizures on awakening (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). These recurrent seizures occur in the absence of detectable brain lesions and/or metabolic abnormalities. Seizures are initially generalized with a bilateral, synchronous, generalized, symmetrical EEG discharge (Zara et al., 1995; Lu and Wang, 2009). See also childhood absence epilepsy (ECA1; 600131), which has also been mapped to 8q24. Of note, benign neonatal epilepsy 2 (EBN2; 121201) is caused by mutation in the KCNQ3 gene (602232) on 8q24. Genetic Heterogeneity of Idiopathic Generalized Epilepsy EIG1 has been mapped to chromosome 8q24. Other loci or genes associated with EIG include EIG2 (606972) on 14q23; EIG3 (608762) on 9q32; EIG4 (609750) on 10q25; EIG5 (611934) on 10p11; EIG6 (611942), caused by mutation in the CACNA1H gene (607904) on 16p; EIG7 (604827) on 15q14; EIG8 (612899), caused by mutation in the CASR gene (601199) on 3q13.3-q21; EIG9 (607682), caused by mutation in the CACNB4 gene (601949) on 2q22-q23; EIG10 (613060), caused by mutation in the GABRD gene (137163) on 1p36.3; EIG11 (607628), caused by variation in the CLCN2 gene (600570) on 3q36; EIG12 (614847), caused by mutation in the SLC2A1 gene (138140) on 1p34; EIG13 (611136), caused by mutation in the GABRA1 gene (137160) on 5q34; EIG14 (616685), caused by mutation in the SLC12A5 gene (606726) on 20q12; and EIG15 (618357), caused by mutation in the RORB gene (601972) on 9q22.
Last Evaluated: Jun 29, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign, risk factor
Assembly: GRCh38
Chromosome/Position: 1:2028260
OMIM Allelic Variant: 137163.0002
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 29, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign, risk factor
Assembly: GRCh38
Chromosome/Position: 1:2028260
OMIM Allelic Variant: 137163.0002
Low clinical importance, Likely benign — Probably benign, one report hypothesized this variant was associated with epilepsy, but a follow-up investigation failed to establish any statistically significant difference for this variant's incidence in control vs. affected populations.
Benign/Likely benign, risk factor
Hetero
Gene:
PTPRQ
Variant:
c.1285C>G
(p.Gln429Glu)
rsID: rs61729287
Ref Allele: C
Alt Allele: G
Freq: 1.5665%uncommon
CADD: 22.9
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 19, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:80484531
Likely benign
Hetero
Gene:
CRPPA
Variant:
c.*3475C>T
rsID: rs80341455
Ref Allele: G
Alt Allele: A
Freq: 1.5689%uncommon
CADD: 0.067
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:16088220
Conflicting/Uncertain
Hetero
Gene:
SZT2
Variant:
c.5364T>G
(p.Ser1788Arg)
rsID: rs114759137
Ref Allele: T
Alt Allele: G
Freq: 1.5904%uncommon
CADD: 4.275
ClinVar Submissions (4)
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:43432732
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:43432732
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:43432732
Benign
Hetero
Gene:
CUBN
Variant:
c.2571C>T
(p.Asn857=)
rsID: rs17432826
Ref Allele: G
Alt Allele: A
Freq: 1.596%uncommon
CADD: 6.775
ClinVar Submissions (1)
A disorder characterized by the presence of ANEMIA, abnormally large red blood cells (megalocytes or macrocytes), and MEGALOBLASTS.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:17071480
Likely benign
Hetero
Gene:
PRX
Variant:
c.471G>A
(p.Glu157=)
rsID: rs4803335
Ref Allele: C
Alt Allele: T
Freq: 1.6159%uncommon
CADD: 9.47
ClinVar Submissions (2)
Charcot-Marie-Tooth disease type 4 (CMT4) belongs to the genetically heterogeneous group of CMT peripheral sensorimotor polyneuropathy diseases. Type 4 is less common and often limited to certain ethnic groups. Patients present with the typical CMT phenotype along with typical features of progressive, distally accentuated weakness and atrophy of muscles innervated by the peroneal nerve in the lower limbs, followed by weakness and atrophy of hands, sensory loss, and characteristic foot abnormalities.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:40397881
Benign
Hetero
Gene:
KIF1B
Variant:
c.2421G>T
(p.Met807Ile)
rsID: rs41274458
Ref Allele: G
Alt Allele: T
Freq: 1.619%uncommon
CADD: 14.83
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 13, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:10303606
Benign
Hetero
Gene:
FBLN5
Variant:
c.1122C>T
(p.Tyr374=)
rsID: rs145515678
Ref Allele: G
Alt Allele: A
Freq: 1.6358%uncommon
CADD: 18.81
ClinVar Submissions (2)
Last Evaluated: Oct 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:91877550
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Oct 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:91877550
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:91877550
Likely benign
Hetero
Gene:
HTRA2
Variant:
c.421G>T
(p.Ala141Ser)
rsID: rs72470544
Ref Allele: G
Alt Allele: T
Freq: 1.6636%uncommon
CADD: 2.914
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:74530427
OMIM Allelic Variant: 606441.0002
Parkinsonism refers to all clinical states characterized by tremor, muscle rigidity, slowed movement (bradykinesia) and often postural instability. Parkinson disease is the primary and most common form of parkinsonism. Psychiatric manifestations, which include depression and visual hallucinations, are common but not uniformly present. Dementia eventually occurs in at least 20% of cases. The most common sporadic form of Parkinson disease manifests around age 60; however, young-onset and even juvenile presentations are seen.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:74530427
OMIM Allelic Variant: 606441.0002
Low clinical importance, Likely benign — Probably benign. One report proposed an association with increased risk for Parkinson's disease, but had very weak statistical significance. A later study found an equal incidence of this variant in cases and controls, contradicting any association with the disease.
Likely benign
Hetero
Gene:
OTOF
Variant:
c.5391C>T
(p.Phe1797=)
rsID: rs61747275
Ref Allele: G
Alt Allele: A
Freq: 1.6668%uncommon
CADD: 16.52
ClinVar Submissions (4)
OTOF-related deafness (DFNB9 nonsyndromic hearing loss) is characterized by two phenotypes: prelingual nonsyndromic hearing loss and, less frequently, temperature-sensitive nonsyndromic auditory neuropathy (TS-NSAN). The nonsyndromic hearing loss is bilateral severe-to-profound congenital deafness. In the first one or two years of life, OTOF-related deafness can appear to be an auditory neuropathy based on electrophysiologic testing in which auditory brain stem responses (ABRs) are absent and otoacoustic emissions (OAEs) are present. However, with time OAEs disappear and electrophysiologic testing is more consistent with a cochlear defect. The distinction between auditory neuropathy and a cochlear defect is important as cochlear implants may be of marginal value in persons with auditory neuropathy but have been shown to be effective for individuals with OTOF-related deafness. TS-NSAN is characterized by normal-to-mild hearing loss in the absence of fever and significant hearing loss ranging from severe to profound in the presence of fever. When the fever resolves, hearing returns to normal.
Last Evaluated: Nov 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:26461838
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:26461838
Benign
Hetero
Gene:
SCN3B
Variant:
c.*2561C>T
rsID: rs72552174
Ref Allele: G
Alt Allele: A
Freq: 1.6804%uncommon
CADD: 1.959
ClinVar Submissions (1)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:123631238
Likely benign
Hetero
Gene:
VPS13A
Variant:
c.9382T>C
(p.Leu3128=)
rsID: rs34255276
Ref Allele: T
Alt Allele: C
Freq: 1.6907%uncommon
CADD: 4.252
ClinVar Submissions (1)
Chorea-acanthocytosis (ChAc) is characterized by a progressive movement disorder, cognitive and behavior changes, a myopathy that can be subclinical, and chronic hyperCKemia in serum. Although the disorder is named for acanthocytosis of the red blood cells, this feature is variable. The movement disorder is mostly limb chorea, but some individuals present with parkinsonism. Dystonia is common and affects the oral region and especially the tongue, causing dysarthria and serious dysphagia with resultant weight loss. Habitual tongue and lip biting are characteristic, as well as tongue protrusion dystonia. Progressive cognitive and behavioral changes resemble those in a frontal lobe syndrome. Seizures are observed in almost half of affected individuals and can be the initial manifestation. Myopathy results in progressive distal muscle wasting and weakness. Mean age of onset in ChAc is about 30 years, although ChAc can develop as early as the first decade or as late as the seventh decade. It runs a chronic progressive course and may lead to major disability within a few years. Life expectancy is reduced, with age of death ranging from 28 to 61 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:77405970
Conflicting/Uncertain
Hetero
Gene:
IMPDH1
Variant:
c.*597G>A
rsID: rs1803821
Ref Allele: C
Alt Allele: T
Freq: 1.6915%uncommon
CADD: 0.001
ClinVar Submissions (1)
Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). Genetic Heterogeneity of Leber Congenital Amaurosis LCA2 (204100) is caused by mutation in the RPE65 gene (RPE65; 180069) on chromosome 1p31. LCA3 (604232) is caused by mutation in the SPATA7 gene (609868) on chromosome 14q31. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14. LCA6 (613826) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. LCA7 (613829) is caused by mutation in the CRX gene (602225) on chromosome 19q13. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31. LCA9 (608553) is caused by mutation in the NMNAT1 gene (608700) on chromosome 1p36. LCA10 (611755) is caused by mutation in the CEP290 gene (610142) on chromosome 12q21 and may account for as many as 21% of cases of LCA. LCA11 (613837) is caused by mutation in the IMPDH1 gene (146690) on chromosome 7q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q32. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. LCA17 (615360) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. LCA18 (see 608133) is caused by mutation in the PRPH2 gene (179605) on chromosome 6p21. Perrault et al. (1999) provided a review of Leber congenital amaurosis, with emphasis on genetic heterogeneity. Wiszniewski et al. (2011) analyzed 13 known LCA genes in 60 LCA probands, and identified homozygous or compound heterozygous mutations in 42 (70%). In addition, a third disease-associated mutant allele at a second locus was identified in 7 (12%) of the 60 patients. Wiszniewski et al. (2011) stated that the significance of the third mutated allele was unknown, but suggested that mutational load might be important to penetrance of the LCA phenotype. Because LCA manifests very early in life and results in profound vision loss, patients with mutations in other syndromic or nonsyndromic eye disease genes may receive an initial diagnosis of LCA, prior to development of syndromic features or before more thorough phenotyping can be performed (see, e.g., Senior-Loken syndrome-5, 609254).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:128392410
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:128392410
Likely benign
Hetero
Gene:
IMPDH1
Variant:
c.*634C>T
rsID: rs1803822
Ref Allele: G
Alt Allele: A
Freq: 1.6947%uncommon
CADD: 16.25
ClinVar Submissions (1)
Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). Genetic Heterogeneity of Leber Congenital Amaurosis LCA2 (204100) is caused by mutation in the RPE65 gene (RPE65; 180069) on chromosome 1p31. LCA3 (604232) is caused by mutation in the SPATA7 gene (609868) on chromosome 14q31. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14. LCA6 (613826) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. LCA7 (613829) is caused by mutation in the CRX gene (602225) on chromosome 19q13. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31. LCA9 (608553) is caused by mutation in the NMNAT1 gene (608700) on chromosome 1p36. LCA10 (611755) is caused by mutation in the CEP290 gene (610142) on chromosome 12q21 and may account for as many as 21% of cases of LCA. LCA11 (613837) is caused by mutation in the IMPDH1 gene (146690) on chromosome 7q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q32. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. LCA17 (615360) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. LCA18 (see 608133) is caused by mutation in the PRPH2 gene (179605) on chromosome 6p21. Perrault et al. (1999) provided a review of Leber congenital amaurosis, with emphasis on genetic heterogeneity. Wiszniewski et al. (2011) analyzed 13 known LCA genes in 60 LCA probands, and identified homozygous or compound heterozygous mutations in 42 (70%). In addition, a third disease-associated mutant allele at a second locus was identified in 7 (12%) of the 60 patients. Wiszniewski et al. (2011) stated that the significance of the third mutated allele was unknown, but suggested that mutational load might be important to penetrance of the LCA phenotype. Because LCA manifests very early in life and results in profound vision loss, patients with mutations in other syndromic or nonsyndromic eye disease genes may receive an initial diagnosis of LCA, prior to development of syndromic features or before more thorough phenotyping can be performed (see, e.g., Senior-Loken syndrome-5, 609254).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:128392373
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:128392373
Likely benign
Hetero
Gene:
PAX8
Variant:
c.985T>C
(p.Phe329Leu)
rsID: rs3188996
Ref Allele: A
Alt Allele: G
Freq: 1.6979%uncommon
CADD: 24.7
ClinVar Submissions (1)
Last Evaluated: Oct 17, 1997
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:113235496
OMIM Allelic Variant: 167415.0001
Benign
Hetero
Gene:
TNXB
Variant:
c.517G>A
(p.Ala173Thr)
rsID: rs61746206
Ref Allele: C
Alt Allele: T
Freq: 1.7154%uncommon
CADD: 6.198
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:32097336
Benign
Hetero
Gene:
PKP2
Variant:
c.209G>T
(p.Ser70Ile)
rsID: rs75909145
Ref Allele: C
Alt Allele: A
Freq: 1.7313%uncommon
CADD: 20.8
ClinVar Submissions (10)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:32896523
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:32896523
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:32896523
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 10
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:32896523
Benign/Likely benign
Hetero
Gene:
CFHR5
Variant:
c.1067G>A
(p.Arg356His)
rsID: rs35662416
Ref Allele: G
Alt Allele: A
Freq: 1.7337%uncommon
CADD: 15.03
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:196998224
Likely benign
Hetero
Gene:
MPDU1
Variant:
c.302+21C>T
rsID: rs74336587
Ref Allele: C
Alt Allele: T
Freq: 1.7449%uncommon
CADD: 2.046
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:7586099
Likely benign
Hetero
Gene:
TBX3
Variant:
c.1173G>C
(p.Ala391=)
rsID: rs146589414
Ref Allele: C
Alt Allele: G
Freq: 1.7528%uncommon
CADD: 4.041
ClinVar Submissions (2)
The ulnar-mammary syndrome is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies (Bamshad et al., 1996).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:114674702
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:114674702
Benign/Likely benign
Hetero
Gene:
SLC17A5
Variant:
c.1111+7G>A
rsID: rs146729568
Ref Allele: C
Alt Allele: T
Freq: 1.7632%uncommon
CADD: 6.046
ClinVar Submissions (3)
The allelic disorders of free sialic acid metabolism – Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD) ? are neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. The mildest phenotype is Salla disease, which is characterized by normal appearance and neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild to moderate psychomotor retardation, spasticity, athetosis, and epileptic seizures. The most severe phenotype is ISSD, characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood.
Last Evaluated: Apr 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:73615308
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 26, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:73615308
Likely benign
Hetero
Gene:
USH2A
Variant:
c.13297G>T
(p.Val4433Leu)
rsID: rs111033381
Ref Allele: C
Alt Allele: A
Freq: 1.7751%uncommon
CADD: 0.78
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 22, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:215674614
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 22, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:215674614
Benign
Hetero
Gene:
PPT1
Variant:
c.124+18T>G
rsID: rs113394351
Ref Allele: A
Alt Allele: C
Freq: 1.7807%uncommon
CADD: 4.75
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:40097097
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:40097097
Benign
Hetero
Gene:
ELMOD3
Variant:
c.549C>T
(p.Thr183=)
rsID: rs115378987
Ref Allele: C
Alt Allele: T
Freq: 1.7807%uncommon
CADD: 0.656
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 25, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:85371504
Likely benign
Hetero
Gene:
PKD1
Variant:
c.12001-34C>A
rsID: rs117865497
Ref Allele: G
Alt Allele: T
Freq: 1.7927%uncommon
CADD: 1.75
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 12, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:2090842
Benign
Hetero
Gene:
SMARCA2
Variant:
c.*431G>A
rsID: rs17387924
Ref Allele: G
Alt Allele: A
Freq: 1.7998%uncommon
CADD: 7.69
ClinVar Submissions (1)
Nicolaides-Baraitser syndrome (NCBRS) is characterized by sparse scalp hair, prominence of the inter-phalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly, seizures, and developmental delay / intellectual disability. Seizures are of various types and can be difficult to manage. Developmental delay / intellectual disability (ID) is severe in nearly a half, moderate in a third, and mild in the remainder. Nearly a third never develop speech or language skills.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:2193170
Likely benign
Hetero
Gene:
C12orf65
Variant:
c.44G>A
(p.Arg15Gln)
rsID: rs78651634
Ref Allele: G
Alt Allele: A
Freq: 1.8046%uncommon
CADD: 13.71
ClinVar Submissions (5)
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:123253718
Spasticity and weakness of the leg and hip muscles.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:123253718
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:123253718
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:123253718
Benign
Hetero
Gene:
GPR179
Variant:
c.5930C>A
(p.Pro1977His)
rsID: rs62073368
Ref Allele: G
Alt Allele: T
Freq: 1.811%uncommon
CADD: 22.2
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:38327639
Likely benign
Hetero
Gene:
PKD2
Variant:
c.596-16C>T
rsID: rs62310565
Ref Allele: C
Alt Allele: T
Freq: 1.8142%uncommon
CADD: 4.171
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 27, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:88019442
Benign
Hetero
Gene:
MIP
Variant:
c.319G>A
(p.Val107Ile)
rsID: rs74641138
Ref Allele: C
Alt Allele: T
Freq: 1.8189%uncommon
CADD: 19.07
ClinVar Submissions (3)
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule. [HPO:probinson]
Last Evaluated: Feb 13, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:56454295
Mutations in the MIP gene have been found to cause multiple types of cataract, which have been described as 'polymorphic,' progressive punctate lamellar, cortical, anterior and posterior polar, nonprogressive lamellar with sutural opacities, embryonic nuclear, and pulverulent cortical.
Last Evaluated: Feb 13, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:56454295
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 13, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:56454295
Benign/Likely benign
Hetero
Gene:
CDON
Variant:
c.2623A>G
(p.Ser875Gly)
rsID: rs115533243
Ref Allele: T
Alt Allele: C
Freq: 1.8197%uncommon
CADD: 23.4
ClinVar Submissions (3)
Last Evaluated: Jan 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:125994311
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Jan 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:125994311
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:125994311
Benign/Likely benign
Hetero
Gene:
ITGA2B
Variant:
c.2094+13C>T
rsID: rs12938868
Ref Allele: G
Alt Allele: A
Freq: 1.8293%uncommon
CADD: 1.181
ClinVar Submissions (2)
Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. The abnormalities are related to quantitative or qualitative abnormalities of the GPIIb/IIIa platelet surface fibrinogen receptor complex resulting from mutations in either the GPIIb or GPIIIa genes (Rosenberg et al., 1997). See 187800 for discussion of a possible dominant form.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:44378349
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:44378349
Benign/Likely benign
Hetero
Gene:
CLN5
Variant:
c.*1132A>G
rsID: rs80200123
Ref Allele: A
Alt Allele: G
Freq: 1.85%uncommon
CADD: 1.407
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:77002101
Likely benign
Hetero
Gene:
CLN5
Variant:
c.528T>G
(p.Thr176=)
rsID: rs34481987
Ref Allele: T
Alt Allele: G
Freq: 1.8516%uncommon
CADD: 15.93
ClinVar Submissions (7)
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:76995943
The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset. The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin): CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage. CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s. Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:76995943
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:76995943
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:76995943
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:76995943
Benign/Likely benign
Hetero
Gene:
PCDH15
Variant:
c.4950G>A
(p.Lys1650=)
rsID: rs74609306
Ref Allele: C
Alt Allele: T
Freq: 1.8611%uncommon
CADD: 5.261
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 07, 2012
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:53806678
Benign
Hetero
Gene:
SMARCB1
Variant:
c.500+305C>A
rsID: rs35502837
Ref Allele: C
Alt Allele: A
Freq: 1.8627%uncommon
CADD: 0.355
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 19, 2013
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 22:23801386
Hetero
Gene:
LRBA
Variant:
c.2170A>G
(p.Ile724Val)
rsID: rs72719663
Ref Allele: T
Alt Allele: C
Freq: 1.8739%uncommon
CADD: 10.56
ClinVar Submissions (1)
Common variable immunodeficiency-8 with autoimmunity is an autosomal recessive disorder of immune dysregulation. Affected individuals have early childhood onset of recurrent infections, particularly respiratory infections, and also develop variable autoimmune disorders, including idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and inflammatory bowel disease. The presentation and phenotype are highly variable, even within families (summary by Lopez-Herrera et al., 2012 and Alangari et al., 2012). Immunologic findings are also variable and may include decreased B cells, hypogammaglobulinemia, and deficiency of CD4+ T regulatory (Treg) cells (Charbonnier et al., 2015). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:150872751
Benign
Hetero
Gene:
SCN1B
Variant:
c.501T>C
(p.Ile167=)
rsID: rs16969930
Ref Allele: T
Alt Allele: C
Freq: 1.8771%uncommon
CADD: 17.31
ClinVar Submissions (5)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35039169
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35039169
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35039169
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35039169
Genetic epilepsy with febrile seizures plus (GEFS+) is a spectrum of seizure disorders of varying severity. GEFS+ is usually diagnosed in families whose members have a combination of febrile seizures, which are triggered by a high fever, and recurrent seizures (epilepsy) of other types, including seizures that are not related to fevers (afebrile seizures). The additional seizure types usually involve both sides of the brain (generalized seizures); however, seizures that involve only one side of the brain (partial seizures) occur in some affected individuals. The most common types of seizure in people with GEFS+ include myoclonic seizures, which cause involuntary muscle twitches; atonic seizures, which involve sudden episodes of weak muscle tone; and absence seizures, which cause loss of consciousness for short periods that appear as staring spells.The most common and mildest feature of the GEFS+ spectrum is simple febrile seizures, which begin in infancy and usually stop by age 5. When the febrile seizures continue after age 5 or other types of seizure develop, the condition is called febrile seizures plus (FS+). Seizures in FS+ usually end in early adolescence.A condition called Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI) is often considered part of the GEFS+ spectrum and is the most severe disorder in this group. Affected infants typically have prolonged seizures lasting several minutes (status epilepticus), which are triggered by fever. Other seizure types, including afebrile seizures, begin in early childhood. These types can include myoclonic or absence seizures. In Dravet syndrome, these seizures are difficult to control with medication, and they can worsen over time. A decline in brain function is also common in Dravet syndrome. Affected individuals usually develop normally in the first year of life, but then development stalls, and some affected children lose already-acquired skills (developmental regression). Many people with Dravet syndrome have difficulty coordinating movements (ataxia) and intellectual disability.Some people with GEFS+ have seizure disorders of intermediate severity that may not fit into the classical diagnosis of simple febrile seizures, FS+, or Dravet syndrome.Family members with GEFS+ may have different combinations of febrile seizures and epilepsy. For example, one affected family member may have only febrile seizures, while another also has myoclonic epilepsy. While GEFS+ is usually diagnosed in families, it can occur in individuals with no history of the condition in their family.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35039169
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35039169
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35039169
Benign/Likely benign
Hetero
Gene:
RP2
Variant:
c.844C>T
(p.Arg282Trp)
rsID: rs1805147
Ref Allele: C
Alt Allele: T
Freq: 1.8858%uncommon
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: X:46860063
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: X:46860063
Benign/Likely benign
Hetero
Gene:
COL10A1
Variant:
c.*246T>C
rsID: rs149788553
Ref Allele: A
Alt Allele: G
Freq: 1.9193%uncommon
CADD: 5.509
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:116119827
Likely benign
Hetero
Gene:
SZT2
Variant:
c.9270-12C>T
rsID: rs115595942
Ref Allele: C
Alt Allele: T
Freq: 1.9225%uncommon
CADD: 0.456
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:43447837
Benign
Hetero
Gene:
ITPR1
Variant:
c.6507A>G
(p.Lys2169=)
rsID: rs34491089
Ref Allele: A
Alt Allele: G
Freq: 1.928%uncommon
CADD: 9.091
ClinVar Submissions (2)
Autosomal dominant cerebellar ataxia (ADCA) describes a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by a slowly progressive ataxia of gait, stance and limbs, dysarthria and/or oculomotor disorder, due to cerebellar degeneration in the absence of coexisting diseases. The degenerative process can be limited to the cerebellum (ADCA type 3) or may additionally involve the retina (ADCA type 2), optic nerve, ponto-medullary systems, basal ganglia, cerebral cortex, spinal tracts or peripheral nerves (ADCA type 1) (see these terms). In ACDA type 4 (see this term), a cerebellar syndrome is associated with epilepsy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:4788027
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:4788027
Likely benign
Hetero
Gene:
KCNQ3
Variant:
c.*1697C>G
rsID: rs71526238
Ref Allele: G
Alt Allele: C
Freq: 1.9288%uncommon
CADD: 0.799
ClinVar Submissions (1)
A condition marked by recurrent seizures that occur during the first 4-6 weeks of life despite an otherwise benign neonatal course. Autosomal dominant familial and sporadic forms have been identified. Seizures generally consist of brief episodes of tonic posturing and other movements, apnea, eye deviations, and blood pressure fluctuations. These tend to remit after the 6th week of life. The risk of developing epilepsy at an older age is moderately increased in the familial form of this disorder. (Neurologia 1996 Feb;11(2):51-5)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:132127565
Benign familial neonatal seizures (BFNS) is a condition characterized by recurrent seizures in newborn babies. The seizures begin around day 3 of life and usually go away within 1 to 4 months. The seizures can involve only one side of the brain (focal seizures) or both sides (generalized seizures). Many infants with this condition have generalized tonic-clonic seizures (also known as grand mal seizures). This type of seizure involves both sides of the brain and affects the entire body, causing muscle rigidity, convulsions, and loss of consciousness.A test called an electroencephalogram (EEG) is used to measure the electrical activity of the brain. Abnormalities on an EEG test, measured during no seizure activity, can indicate a risk for seizures. However, infants with BFNS usually have normal EEG readings. In some affected individuals, the EEG shows a specific abnormality called the theta pointu alternant pattern. By age 2, most affected individuals who had EEG abnormalities have a normal EEG reading.Typically, seizures are the only symptom of BFNS, and most people with this condition develop normally. However, some affected individuals develop intellectual disability that becomes noticeable in early childhood. A small percentage of people with BFNS also have a condition called myokymia, which is an involuntary rippling movement of the muscles. In addition, in about 15 percent of people with BFNS, recurrent seizures (epilepsy) will come back later in life after the seizures associated with BFNS have gone away. The age that epilepsy begins is variable.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:132127565
Likely benign
Hetero
Gene:
KCNQ3
Variant:
c.*7464C>A
rsID: rs35604597
Ref Allele: G
Alt Allele: T
Freq: 1.9296%uncommon
CADD: 1.27
ClinVar Submissions (1)
A condition marked by recurrent seizures that occur during the first 4-6 weeks of life despite an otherwise benign neonatal course. Autosomal dominant familial and sporadic forms have been identified. Seizures generally consist of brief episodes of tonic posturing and other movements, apnea, eye deviations, and blood pressure fluctuations. These tend to remit after the 6th week of life. The risk of developing epilepsy at an older age is moderately increased in the familial form of this disorder. (Neurologia 1996 Feb;11(2):51-5)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:132121798
Benign familial neonatal seizures (BFNS) is a condition characterized by recurrent seizures in newborn babies. The seizures begin around day 3 of life and usually go away within 1 to 4 months. The seizures can involve only one side of the brain (focal seizures) or both sides (generalized seizures). Many infants with this condition have generalized tonic-clonic seizures (also known as grand mal seizures). This type of seizure involves both sides of the brain and affects the entire body, causing muscle rigidity, convulsions, and loss of consciousness.A test called an electroencephalogram (EEG) is used to measure the electrical activity of the brain. Abnormalities on an EEG test, measured during no seizure activity, can indicate a risk for seizures. However, infants with BFNS usually have normal EEG readings. In some affected individuals, the EEG shows a specific abnormality called the theta pointu alternant pattern. By age 2, most affected individuals who had EEG abnormalities have a normal EEG reading.Typically, seizures are the only symptom of BFNS, and most people with this condition develop normally. However, some affected individuals develop intellectual disability that becomes noticeable in early childhood. A small percentage of people with BFNS also have a condition called myokymia, which is an involuntary rippling movement of the muscles. In addition, in about 15 percent of people with BFNS, recurrent seizures (epilepsy) will come back later in life after the seizures associated with BFNS have gone away. The age that epilepsy begins is variable.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:132121798
Likely benign
Hetero
Gene:
RBM8A
Variant:
c.-21G>A
rsID: rs139428292
Ref Allele: C
Alt Allele: T
Freq: 1.9456%uncommon
CADD: 8.717
ClinVar Submissions (7)
Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia (<50 platelets/nL) that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.
Last Evaluated: May 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Pathogenic/Likely pathogenic, other
Assembly: GRCh38
Chromosome/Position: 1:145927447
OMIM Allelic Variant: 605313.0001
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Pathogenic/Likely pathogenic, other
Assembly: GRCh38
Chromosome/Position: 1:145927447
OMIM Allelic Variant: 605313.0001
Clinically Significant Pathogenic/Likely pathogenic, other
Hetero
Gene:
CSF3R
Variant:
c.958G>A
(p.Asp320Asn)
rsID: rs3918018
Ref Allele: C
Alt Allele: T
Freq: 1.9559%uncommon
CADD: 4.783
ClinVar Submissions (2)
Severe congenital neutropenia-7 is an autosomal recessive immunodeficiency characterized by onset of recurrent infections in infancy or early childhood. Patients have peripheral neutropenia, although bone marrow biopsy shows normal granulocyte maturation. The neutropenia is not responsive to treatment with G-CSF, but may be responsive to GM-CSF (summary by Triot et al., 2014 and Klimiankou et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (202700).
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:36472277
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:36472277
Benign
Hetero
Gene:
LRP2
Variant:
c.6035G>A
(p.Arg2012Lys)
rsID: rs4667596
Ref Allele: C
Alt Allele: T
Freq: 1.9671%uncommon
CADD: 18.37
ClinVar Submissions (2)
Donnai-Barrow syndrome (DBS) is characterized by typical craniofacial features (large anterior fontanel, wide metopic suture, widow's peak, markedly widely spaced eyes, enlarged globes, downslanted palpebral fissures, posteriorly rotated ears, depressed nasal bridge, and short nose. Ocular complications include high myopia, retinal detachment, retinal dystrophy, and progressive vision loss. Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele. Both inter- and intrafamilial phenotypic variability are observed.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:169213662
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:169213662
Benign/Likely benign
Hetero
Gene:
ZFYVE27
Variant:
c.378G>A
(p.Lys126=)
rsID: rs75060573
Ref Allele: G
Alt Allele: A
Freq: 1.987%uncommon
CADD: 10.21
ClinVar Submissions (4)
Spasticity and weakness of the leg and hip muscles.
Last Evaluated: Jul 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:97744838
Last Evaluated: Jul 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:97744838
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:97744838
Benign/Likely benign
Hetero
Gene:
SLC13A5
Variant:
c.-17A>C
rsID: rs62061545
Ref Allele: T
Alt Allele: G
Freq: 2.0037%uncommon
CADD: 10.81
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 15, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:6713350
Benign
Hetero
Gene:
KCNQ3
Variant:
c.*2166A>G
rsID: rs35279095
Ref Allele: T
Alt Allele: C
Freq: 2.0061%uncommon
CADD: 0.73
ClinVar Submissions (1)
A condition marked by recurrent seizures that occur during the first 4-6 weeks of life despite an otherwise benign neonatal course. Autosomal dominant familial and sporadic forms have been identified. Seizures generally consist of brief episodes of tonic posturing and other movements, apnea, eye deviations, and blood pressure fluctuations. These tend to remit after the 6th week of life. The risk of developing epilepsy at an older age is moderately increased in the familial form of this disorder. (Neurologia 1996 Feb;11(2):51-5)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:132127096
Benign familial neonatal seizures (BFNS) is a condition characterized by recurrent seizures in newborn babies. The seizures begin around day 3 of life and usually go away within 1 to 4 months. The seizures can involve only one side of the brain (focal seizures) or both sides (generalized seizures). Many infants with this condition have generalized tonic-clonic seizures (also known as grand mal seizures). This type of seizure involves both sides of the brain and affects the entire body, causing muscle rigidity, convulsions, and loss of consciousness.A test called an electroencephalogram (EEG) is used to measure the electrical activity of the brain. Abnormalities on an EEG test, measured during no seizure activity, can indicate a risk for seizures. However, infants with BFNS usually have normal EEG readings. In some affected individuals, the EEG shows a specific abnormality called the theta pointu alternant pattern. By age 2, most affected individuals who had EEG abnormalities have a normal EEG reading.Typically, seizures are the only symptom of BFNS, and most people with this condition develop normally. However, some affected individuals develop intellectual disability that becomes noticeable in early childhood. A small percentage of people with BFNS also have a condition called myokymia, which is an involuntary rippling movement of the muscles. In addition, in about 15 percent of people with BFNS, recurrent seizures (epilepsy) will come back later in life after the seizures associated with BFNS have gone away. The age that epilepsy begins is variable.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:132127096
Likely benign
Hetero
Gene:
SPINK5
Variant:
c.2915A>G
(p.His972Arg)
rsID: rs17705005
Ref Allele: A
Alt Allele: G
Freq: 2.0164%uncommon
CADD: 9.014
ClinVar Submissions (2)
Netherton syndrome is a rare and severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Generalized scaly erythroderma is apparent at or soon after birth and usually persists. Scalp hair is sparse and brittle with a characteristic 'bamboo' shape under light microscopic examination due to invagination of the distal part of the hair shaft to its proximal part. Atopic manifestations include eczema-like rashes, atopic dermatitis, pruritus, hay fever, angioedema, urticaria, high levels of IgE in the serum, and hypereosinophilia. Life-threatening complications are frequent during the neonatal period, including hypernatremic dehydration, hypothermia, extreme weight loss, bronchopneumonia, and sepsis. During childhood, failure to thrive is common as a result of malnutrition, metabolic disorders, chronic erythroderma, persistent cutaneous infections, or enteropathy (summary by Bitoun et al., 2002).
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:148127030
Benign/Likely benign
Hetero
Gene:
COL5A2
Variant:
c.*2131T>A
rsID: rs113513554
Ref Allele: A
Alt Allele: T
Freq: 2.0324%uncommon
CADD: 2.285
ClinVar Submissions (1)
Ehlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.The various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were discovered more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.An unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.Many people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.Some forms of Ehlers-Danlos syndrome, notably the vascular type and to a lesser extent the kyphoscoliotic, classical, and classical-like types, can cause unpredictable tearing (rupture) of blood vessels, leading to internal bleeding and other potentially life-threatening complications. The vascular type of Ehlers-Danlos syndrome is also associated with an increased risk of organ rupture, including tearing of the intestine and rupture of the uterus during pregnancy.Other types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:189031939
Likely benign
Hetero
Gene:
SLC5A5
Variant:
c.1626C>T
(p.Cys542=)
rsID: rs45602038
Ref Allele: C
Alt Allele: T
Freq: 2.0531%uncommon
CADD: 0.044
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 19:17888430
Conflicting/Uncertain
Hetero
Gene:
C2;CFB
Variant:
c.1365C>T
(p.Val455=)
rsID: rs2072634
Ref Allele: C
Alt Allele: T
Freq: 2.0722%uncommon
CADD: 14.54
ClinVar Submissions (1)
Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31949514
Complement component 2 deficiency is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria and viruses. People with complement component 2 deficiency have a significantly increased risk of recurrent bacterial infections, specifically of the lungs (pneumonia), the membrane covering the brain and spinal cord (meningitis), and the blood (sepsis), which may be life-threatening. These infections most commonly occur in infancy and childhood and become less frequent in adolescence and adulthood.Complement component 2 deficiency is also associated with an increased risk of developing autoimmune disorders such as systemic lupus erythematosus (SLE) or vasculitis. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. Between 10 and 20 percent of individuals with complement component 2 deficiency develop SLE. Females with complement component 2 deficiency are more likely to have SLE than affected males, but this is also true of SLE in the general population.The severity of complement component 2 deficiency varies widely. While some affected individuals experience recurrent infections and other immune system difficulties, others do not have any health problems related to the disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31949514
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31949514
Benign/Likely benign
Hetero
Gene:
TGFBR2
Variant:
c.*1833A>C
rsID: rs1803446
Ref Allele: A
Alt Allele: C
Freq: 2.0778%uncommon
CADD: 2.973
ClinVar Submissions (1)
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:30693432
Marfan syndrome, a systemic disorder of connective tissue with a high degree of clinical variability, comprises a broad phenotypic continuum ranging from mild (features of Marfan syndrome in one or a few systems) to severe and rapidly progressive neonatal multiorgan disease. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Ocular findings include myopia (the most common ocular feature); ectopia lentis (seen in approximately 60% of affected individuals); and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity; disproportionately long extremities for the size of the trunk (dolichostenomelia); overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum); and scoliosis that ranges from mild to severe and progressive. The major morbidity and early mortality in the Marfan syndrome relate to the cardiovascular system and include dilatation of the aorta at the level of the sinuses of Valsalva (predisposing to aortic tear and rupture), mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Severe and prolonged regurgitation of the mitral and/or aortic valve can predispose to left ventricular dysfunction and occasionally heart failure. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:30693432
Familial thoracic aortic aneurysm and dissection (familial TAAD) involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax). Other vessels that carry blood from the heart to the rest of the body (arteries) can also be affected.In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), which can lead to a bulge in the blood vessel wall (an aneurysm). Aortic dilatation may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers. These aortic abnormalities are potentially life-threatening because they can decrease blood flow to other parts of the body such as the brain or other vital organs, or cause the aorta to break open (rupture).The occurrence and timing of these aortic abnormalities vary, even within the same affected family. They can begin in childhood or not occur until late in life. Aortic dilatation is generally the first feature of familial TAAD to develop, although in some affected individuals dissection occurs with little or no aortic dilatation.Aortic aneurysms usually have no symptoms. However, depending on the size, growth rate, and location of these abnormalities, they can cause pain in the jaw, neck, chest, or back; swelling in the arms, neck, or head; difficult or painful swallowing; hoarseness; shortness of breath; wheezing; a chronic cough; or coughing up blood. Aortic dissections usually cause severe, sudden chest or back pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias) in one or more limbs, or paralysis.Familial TAAD may not be associated with other signs and symptoms. However, some individuals in affected families show mild features of related conditions called Marfan syndrome or Loeys-Dietz syndrome. These features include tall stature, stretch marks on the skin, an unusually large range of joint movement (joint hypermobility), and either a sunken or protruding chest. Occasionally, people with familial TAAD develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have heart abnormalities that are present from birth (congenital). Affected individuals may also have a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries). However, these conditions are also common in the general population. Depending on the genetic cause of familial TAAD in particular families, they may have an increased risk of developing blockages in smaller arteries, which can lead to heart attack and stroke.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:30693432
Likely benign
Hetero
Gene:
AHI1
Variant:
c.1780-47C>T
rsID: rs17053651
Ref Allele: G
Alt Allele: A
Freq: 2.1025%uncommon
CADD: 0.1
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:135442761
Benign
Hetero
Gene:
PEX19
Variant:
c.*898A>G
rsID: rs8989
Ref Allele: T
Alt Allele: C
Freq: 2.1335%uncommon
CADD: 11.55
ClinVar Submissions (1)
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term ZSD is now used to refer to all individuals with a PEX gene defect regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and other long bones), and liver disease which can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss); neurologic involvement (ataxia, polyneuropathy, and leukodystrophy); liver dysfunction; adrenal insufficiency; and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:160278653
Conflicting/Uncertain
Hetero
Gene:
WT1
Variant:
c.*835A>G
rsID: rs5030322
Ref Allele: T
Alt Allele: C
Freq: 2.1359%uncommon
CADD: 10.2
ClinVar Submissions (1)
Nephrotic syndrome, a malfunction of the glomerular filter, leads to proteinuria, edema, and, in steroid-resistant nephrotic syndrome, end-stage renal disease (ESRD). Renal histopathology in NPHS4 due to WT1 mutations most often shows diffuse mesangial sclerosis (DMS), but can also show focal segmental glomerulosclerosis (FSGS). Both of these terms refer to pathologic findings and may be associated with the same clinical phenotype, namely nephrotic syndrome (review by Schumacher et al., 1998). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32388223
A multiple malformation syndrome with characteristics of congenital diaphragmatic abnormalities, genital defects and cardiac malformations. Less than 15 patients have been reported worldwide. Ambiguous or female external genitalia are present in individuals with 46,XY karyotype. The genital abnormalities are variable and may include a true double vagina or septate vagina, absent uterus, abnormal male gonads in the presence of normal external female genitalia or male pseudohermaphroditism with abnormal internal female genitalia. Complex cyanotic congenital heart defects, (hypoplastic right lungs, anomalous pulmonary venous return and abnormalities of the diaphragm) are frequent. One patient with rhabdomyomatous dysplasia of the lungs has been reported. Mutations in the WT1 gene have been identified in some patients with Meacham syndrome. All patients reported to date died in early childhood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32388223
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32388223
PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:32388223
Likely benign
Hetero
Gene:
MOCS1
Variant:
c.*173G>A
rsID: rs41273142
Ref Allele: C
Alt Allele: T
Freq: 2.1534%uncommon
CADD: 0.146
ClinVar Submissions (1)
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor Deficiency See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:39906952
Likely benign
Hetero
Gene:
MYH3
Variant:
c.5457+3G>A
rsID: rs200954595
Ref Allele: C
Alt Allele: T
Freq: 2.1582%uncommon
CADD: 10.14
ClinVar Submissions (3)
A non-progressive finding characterized by multiple joint contractures found throughout the body at birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10630285
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10630285
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10630285
Benign/Likely benign
Hetero
Gene:
CARD14
Variant:
c.1264G>A
(p.Glu422Lys)
rsID: rs61751629
Ref Allele: G
Alt Allele: A
Freq: 2.2546%uncommon
CADD: 19.74
ClinVar Submissions (1)
Pityriasis rubra pilaris is an uncommon skin disorder characterized by the appearance of keratotic follicular papules, well-demarcated salmon-colored erythematous plaques covered with fine powdery scales interspersed with distinct islands of uninvolved skin, and palmoplantar keratoderma. Most cases are sporadic, although up to 6.5% of PRP-affected individuals report a positive family history. The rare familial cases show autosomal dominant inheritance with incomplete penetrance and variable expression: the disorder is usually present at birth or appears during the first years of life and is characterized by prominent follicular hyperkeratosis, diffuse palmoplantar keratoderma, and erythema, with only a modest response to treatment (summary by Fuchs-Telem et al., 2012).
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:80192527
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:80192527
Benign
Hetero
Gene:
NKX2-6
Variant:
c.386C>A
(p.Ala129Glu)
rsID: rs143039156
Ref Allele: G
Alt Allele: T
Freq: 2.2593%uncommon
CADD: 4.444
ClinVar Submissions (1)
Last Evaluated: Jul 26, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:23702971
Benign
Hetero
Gene:
RAD51B
Variant:
c.1094C>G
(p.Pro365Arg)
rsID: rs28908468
Ref Allele: C
Alt Allele: G
Freq: 2.2665%uncommon
CADD: 0.647
ClinVar Submissions (1)
Last Evaluated: Nov 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 14:68594542
drug response
Hetero
Gene:
RARS2
Variant:
c.991A>G
(p.Ile331Val)
rsID: rs3757370
Ref Allele: T
Alt Allele: C
Freq: 2.2713%uncommon
CADD: 16.47
ClinVar Submissions (5)
Pontocerebellar hypoplasia is a group of related conditions that affect the development of the brain. The term "pontocerebellar" refers to the pons and the cerebellum, which are the brain structures that are most severely affected in many forms of this disorder. The pons is located at the base of the brain in an area called the brainstem, where it transmits signals between the cerebellum and the rest of the brain. The cerebellum, which is located at the back of the brain, normally coordinates movement. The term "hypoplasia" refers to the underdevelopment of these brain regions.Pontocerebellar hypoplasia also causes impaired growth of other parts of the brain, leading to an unusually small head size (microcephaly). This microcephaly is usually not apparent at birth but becomes noticeable as brain growth continues to be slow in infancy and early childhood.Researchers have described at least ten types of pontocerebellar hypoplasia. All forms of this condition are characterized by impaired brain development, delayed development overall, problems with movement, and intellectual disability. The brain abnormalities are usually present at birth, and in some cases they can be detected before birth. Many children with pontocerebellar hypoplasia live only into infancy or childhood, although some affected individuals have lived into adulthood.The two major forms of pontocerebellar hypoplasia are designated as type 1 (PCH1) and type 2 (PCH2). In addition to the brain abnormalities described above, PCH1 causes problems with muscle movement resulting from a loss of specialized nerve cells called motor neurons in the spinal cord, similar to another genetic disorder known as spinal muscular atrophy. Individuals with PCH1 also have very weak muscle tone (hypotonia), joint deformities called contractures, vision impairment, and breathing and feeding problems that are evident from early infancy.Common features of PCH2 include a lack of voluntary motor skills (such as grasping objects, sitting, or walking), problems with swallowing (dysphagia), and an absence of communication, including speech. Affected children typically develop temporary jitteriness (generalized clonus) in early infancy, abnormal patterns of movement described as chorea or dystonia, and stiffness (spasticity). Many also have impaired vision and seizures.The other forms of pontocerebellar hypoplasia, designated as type 3 (PCH3) through type 10 (PCH10), appear to be rare and have each been reported in only a small number of individuals. Because the different types have overlapping features, and some are caused by mutations in the same genes, researchers have proposed that the types be considered as a spectrum instead of distinct conditions.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:87521508
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:87521508
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:87521508
Benign/Likely benign
Hetero
Gene:
COL2A1
Variant:
c.532-27T>A
rsID: rs41317883
Ref Allele: A
Alt Allele: T
Freq: 2.2888%uncommon
CADD: 2.399
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:47996652
Benign
Hetero
Gene:
MAK
Variant:
c.843C>T
(p.His281=)
rsID: rs55950618
Ref Allele: G
Alt Allele: A
Freq: 2.3008%uncommon
CADD: 18.27
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:10796298
Conflicting/Uncertain
Hetero
Gene:
EP300
Variant:
c.2131+18T>A
rsID: rs9611506
Ref Allele: T
Alt Allele: A
Freq: 2.3023%uncommon
CADD: 0.83
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 09, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:41146834
Benign
Hetero
Gene:
FGF3
Variant:
c.325-5C>T
rsID: rs61749187
Ref Allele: G
Alt Allele: A
Freq: 2.3103%uncommon
CADD: 11.86
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:69810705
Benign
Hetero
Gene:
CD40LG
Variant:
c.-191A>C
rsID: rs36206512
Ref Allele: A
Alt Allele: C
Freq: 2.3143%uncommon
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 23, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: X:136648058
Benign/Likely benign
Hetero
Gene:
LOXHD1
Variant:
c.2T>A
(p.Met1Lys)
rsID: rs36024592
Ref Allele: A
Alt Allele: T
Freq: 2.3167%uncommon
CADD: 21.6
ClinVar Submissions (3)
Last Evaluated: Aug 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:46657032
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:46657032
Benign
Homo
Gene:
POLE
Variant:
c.3582+17A>G
rsID: rs5744889
Ref Allele: T
Alt Allele: C
Freq: 2.3342%uncommon
CADD: 0.313
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 03, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:132657119
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 03, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:132657119
Benign
Hetero
Gene:
ALS2
Variant:
c.3885G>A
(p.Ala1295=)
rsID: rs34946105
Ref Allele: C
Alt Allele: T
Freq: 2.3581%uncommon
CADD: 5.414
ClinVar Submissions (3)
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201715791
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201715791
ALS2-related disorders involve retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprise a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP), to juvenile forms without lower motor neuron involvement (juvenile primary lateral sclerosis [JPLS]), to forms with lower motor neuron involvement (autosomal recessive juvenile amyotrophic lateral sclerosis [JALS]). IAHSP is characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive weakness and spasticity of the upper limbs by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome. JPLS is characterized by onset and loss of ability to walk during the second year of life, progressive signs of upper motor neuron disease, wheelchair dependence by adolescence, and later loss of motor speech production. JALS is characterized by onset during childhood (mean age of onset 6.5 years), spasticity of facial muscles, uncontrolled laughter, spastic dysarthria, spastic gait, moderate muscle atrophy (variably present), bladder dysfunction, and sensory disturbances; some individuals are bedridden by age 12 to 50 years.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201715791
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201715791
Benign/Likely benign
Hetero
Gene:
CDON
Variant:
c.*3076T>A
rsID: rs73019370
Ref Allele: A
Alt Allele: T
Freq: 2.3653%uncommon
CADD: 0.075
ClinVar Submissions (1)
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:125957866
Likely benign
Hetero
Gene:
CCT5
Variant:
c.738G>A
(p.Ala246=)
rsID: rs11557649
Ref Allele: G
Alt Allele: A
Freq: 2.3748%uncommon
CADD: 1.817
ClinVar Submissions (2)
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:10258400
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:10258400
Benign/Likely benign
Hetero
Gene:
ALG9
Variant:
c.406-7C>T
rsID: rs45574638
Ref Allele: G
Alt Allele: A
Freq: 2.3891%uncommon
CADD: 16.55
ClinVar Submissions (3)
Congenital disorders of glycosylation (CDGs) that represent defects of dolichol-linked oligosaccharide assembly are classified as CDG type I. For a general description and a discussion of the classification of CDGs, see CDG1A (212065).
Last Evaluated: Mar 13, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:111865258
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 13, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:111865258
Benign
Hetero
Gene:
MOCS1
Variant:
c.*1502C>G
rsID: rs1063171
Ref Allele: G
Alt Allele: C
Freq: 2.3899%uncommon
CADD: 1.274
ClinVar Submissions (1)
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor Deficiency See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:39905623
Likely benign
Hetero
Gene:
UBIAD1
Variant:
c.*148A>G
rsID: rs11580061
Ref Allele: A
Alt Allele: G
Freq: 2.3963%uncommon
CADD: 7.633
ClinVar Submissions (1)
Schnyder corneal dystrophy (SCCD), also known as Schnyder crystalline corneal dystrophy, is an autosomal dominant eye disease characterized by abnormal deposition of cholesterol and phospholipids in the cornea. The consequent corneal opacification is progressive and bilateral, resulting in glare and loss of vision that is postulated to be caused by light scattering. Patients demonstrate a characteristic pattern of corneal opacification dependent on age, and only half have crystalline corneal cholesterol deposits. Patients with noncrystalline disease have a more subtle presentation with only corneal haze, which may be difficult to diagnose (summary by Nickerson et al., 2013).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:11286279
Likely benign
Hetero
Gene:
POLE
Variant:
c.3379-5T>C
rsID: rs5744886
Ref Allele: A
Alt Allele: G
Freq: 2.4306%uncommon
CADD: 5.726
ClinVar Submissions (7)
Colorectal cancer-12 is an autosomal dominant disorder characterized by a high-penetrance predisposition to the development of colorectal adenomas and carcinomas, with a variable tendency to develop multiple and large tumors. Onset usually occurs before age 40 years. The histologic features of the tumors may be unremarkable (Palles et al., 2013) or show microsatellite instability (MSI) (Elsayed et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of colorectal cancer, see 114500.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:132657434
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:132657434
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:132657434
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:132657434
Benign
Hetero
Gene:
VPS13A
Variant:
c.*942C>T
rsID: rs1048743
Ref Allele: C
Alt Allele: T
Freq: 2.4322%uncommon
CADD: 1.661
ClinVar Submissions (1)
Chorea-acanthocytosis (ChAc) is characterized by a progressive movement disorder, cognitive and behavior changes, a myopathy that can be subclinical, and chronic hyperCKemia in serum. Although the disorder is named for acanthocytosis of the red blood cells, this feature is variable. The movement disorder is mostly limb chorea, but some individuals present with parkinsonism. Dystonia is common and affects the oral region and especially the tongue, causing dysarthria and serious dysphagia with resultant weight loss. Habitual tongue and lip biting are characteristic, as well as tongue protrusion dystonia. Progressive cognitive and behavioral changes resemble those in a frontal lobe syndrome. Seizures are observed in almost half of affected individuals and can be the initial manifestation. Myopathy results in progressive distal muscle wasting and weakness. Mean age of onset in ChAc is about 30 years, although ChAc can develop as early as the first decade or as late as the seventh decade. It runs a chronic progressive course and may lead to major disability within a few years. Life expectancy is reduced, with age of death ranging from 28 to 61 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:77416948
Likely benign
Hetero
Gene:
NPHP1
Variant:
c.115C>A
(p.Pro39Thr)
rsID: rs33958626
Ref Allele: G
Alt Allele: T
Freq: 2.4481%uncommon
CADD: 11.36
ClinVar Submissions (6)
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Last Evaluated: Apr 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:110201449
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Apr 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:110201449
Senior-Loken syndrome is an autosomal recessive disease with the main features of nephronophthisis (NPHP; see 256100) and Leber congenital amaurosis (see 204000). Mutations in some of the same genes that cause nephronophthisis (see 256100) cause Senior-Loken syndrome. Genetic Heterogeneity of Senior-Loken Syndrome Other forms of SLSN include SLSN4 (606996), caused by mutation in the NPHP4 gene (607215) on chromosome 1p36; SLSN5 (609254), caused by mutation in the NPHP5 gene (IQCB1; 609237) on chromosome 3q13; SLSN6 (610189), caused by mutation in the NPHP6 gene (CEP290; 610142) on chromosome 12q21; SLSN7 (613615), caused by mutation in the SDCCAG8 gene (613524) on chromosome 1q43; SLSN8 (616307), caused by mutation in the WDR19 gene (608151) on chromosome 4p14; and SLSN9 (616629), caused by mutation in the TRAF3IP1 gene (607380) on chromosome 2q37. Another form of SLSN, SLSN3 (606995), has been mapped to a locus on chromosome 3q22, overlapping the NPHP3 locus (604387).
Last Evaluated: Apr 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:110201449
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:110201449
Benign/Likely benign
Hetero
Gene:
CDON
Variant:
c.*2003C>G
rsID: rs73019373
Ref Allele: G
Alt Allele: C
Freq: 2.46%uncommon
CADD: 0.466
ClinVar Submissions (1)
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:125958939
Likely benign
Hetero
Gene:
ALX4
Variant:
c.*3405G>A
rsID: rs7115841
Ref Allele: C
Alt Allele: T
Freq: 2.4752%uncommon
CADD: 2.049
ClinVar Submissions (1)
Enlarged parietal foramina is an inherited condition of impaired skull development. It is characterized by enlarged openings (foramina) in the parietal bones, which are the two bones that form the top and sides of the skull. This condition is due to incomplete bone formation (ossification) within the parietal bones. The openings are symmetrical and circular in shape, ranging in size from a few millimeters to several centimeters wide. Parietal foramina are a normal feature of fetal development, but typically they close before the baby is born, usually by the fifth month of pregnancy. However, in people with this condition, the parietal foramina remain open throughout life.The enlarged parietal foramina are soft to the touch due to the lack of bone at those areas of the skull. People with enlarged parietal foramina usually do not have any related health problems; however, scalp defects, seizures, and structural brain abnormalities have been noted in a small percentage of affected people. Pressure applied to the openings can lead to severe headaches, and individuals with this condition have an increased risk of brain damage or skull fractures if any trauma is experienced in the area of the openings.There are two forms of enlarged parietal foramina, called type 1 and type 2, which differ in their genetic cause.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:44261449
Likely benign
Hetero
Gene:
MYLK
Variant:
c.4194C>T
(p.His1398=)
rsID: rs17298941
Ref Allele: G
Alt Allele: A
Freq: 2.511%uncommon
CADD: 5.023
ClinVar Submissions (7)
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
Familial thoracic aortic aneurysm and dissection (familial TAAD) involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax). Other vessels that carry blood from the heart to the rest of the body (arteries) can also be affected.In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), which can lead to a bulge in the blood vessel wall (an aneurysm). Aortic dilatation may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers. These aortic abnormalities are potentially life-threatening because they can decrease blood flow to other parts of the body such as the brain or other vital organs, or cause the aorta to break open (rupture).The occurrence and timing of these aortic abnormalities vary, even within the same affected family. They can begin in childhood or not occur until late in life. Aortic dilatation is generally the first feature of familial TAAD to develop, although in some affected individuals dissection occurs with little or no aortic dilatation.Aortic aneurysms usually have no symptoms. However, depending on the size, growth rate, and location of these abnormalities, they can cause pain in the jaw, neck, chest, or back; swelling in the arms, neck, or head; difficult or painful swallowing; hoarseness; shortness of breath; wheezing; a chronic cough; or coughing up blood. Aortic dissections usually cause severe, sudden chest or back pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias) in one or more limbs, or paralysis.Familial TAAD may not be associated with other signs and symptoms. However, some individuals in affected families show mild features of related conditions called Marfan syndrome or Loeys-Dietz syndrome. These features include tall stature, stretch marks on the skin, an unusually large range of joint movement (joint hypermobility), and either a sunken or protruding chest. Occasionally, people with familial TAAD develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have heart abnormalities that are present from birth (congenital). Affected individuals may also have a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries). However, these conditions are also common in the general population. Depending on the genetic cause of familial TAAD in particular families, they may have an increased risk of developing blockages in smaller arteries, which can lead to heart attack and stroke.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
Benign/Likely benign
Hetero
Gene:
LCA5
Variant:
c.*1300G>A
rsID: rs16890805
Ref Allele: C
Alt Allele: T
Freq: 2.5126%uncommon
CADD: 0.281
ClinVar Submissions (1)
Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). Genetic Heterogeneity of Leber Congenital Amaurosis LCA2 (204100) is caused by mutation in the RPE65 gene (RPE65; 180069) on chromosome 1p31. LCA3 (604232) is caused by mutation in the SPATA7 gene (609868) on chromosome 14q31. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14. LCA6 (613826) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. LCA7 (613829) is caused by mutation in the CRX gene (602225) on chromosome 19q13. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31. LCA9 (608553) is caused by mutation in the NMNAT1 gene (608700) on chromosome 1p36. LCA10 (611755) is caused by mutation in the CEP290 gene (610142) on chromosome 12q21 and may account for as many as 21% of cases of LCA. LCA11 (613837) is caused by mutation in the IMPDH1 gene (146690) on chromosome 7q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q32. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. LCA17 (615360) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. LCA18 (see 608133) is caused by mutation in the PRPH2 gene (179605) on chromosome 6p21. Perrault et al. (1999) provided a review of Leber congenital amaurosis, with emphasis on genetic heterogeneity. Wiszniewski et al. (2011) analyzed 13 known LCA genes in 60 LCA probands, and identified homozygous or compound heterozygous mutations in 42 (70%). In addition, a third disease-associated mutant allele at a second locus was identified in 7 (12%) of the 60 patients. Wiszniewski et al. (2011) stated that the significance of the third mutated allele was unknown, but suggested that mutational load might be important to penetrance of the LCA phenotype. Because LCA manifests very early in life and results in profound vision loss, patients with mutations in other syndromic or nonsyndromic eye disease genes may receive an initial diagnosis of LCA, prior to development of syndromic features or before more thorough phenotyping can be performed (see, e.g., Senior-Loken syndrome-5, 609254).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:79485704
Conflicting/Uncertain
Hetero
Gene:
BTD
Variant:
c.1336G>C
(p.Asp446His)
rsID: rs13078881
Ref Allele: G
Alt Allele: C
Freq: 2.5667%uncommon
CADD: 23.3
ClinVar Submissions (15)
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 05, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 15
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:15645186
OMIM Allelic Variant: 609019.0005
Low clinical importance, pathogenic — This variant is implicated in partial and profound biotinidase deficiency. Alone, this variant is estimated to have a 52% loss of enzymatic activity. This variant is often found with A171T, and together they are reported to cause profound deficiency. Notably there is a report of asymptomatic double-mutant adults, so symptoms may have variable penetrance. This variant is found compound heterozygously with more serious mutations in cases of partial biotinidase deficiency.
Expert Reviewed Clinically Significant Conflicting/Uncertain
Hetero
Gene:
CHRND
Variant:
c.*1025A>G
rsID: rs115132742
Ref Allele: A
Alt Allele: G
Freq: 2.5763%uncommon
CADD: 2.174
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:232536337
Multiple pterygium syndromes comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis) (Morgan et al., 2006). The multiple pterygium syndromes are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal (253290) and nonlethal (Escobar) types.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:232536337
Likely benign
Hetero
Gene:
ATP7B
Variant:
c.3045G>A
(p.Leu1015=)
rsID: rs1801248
Ref Allele: C
Alt Allele: T
Freq: 2.5819%uncommon
CADD: 8.089
ClinVar Submissions (6)
Wilson disease is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances, or a combination of these, in individuals ranging from age three years to older than 50 years; symptoms vary among and within families. Liver disease includes recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmune-type hepatitis, fulminant hepatic failure, or chronic liver disease. Neurologic presentations include movement disorders (tremors, poor coordination, loss of fine-motor control, chorea, choreoathetosis) or rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement). Psychiatric disturbance includes depression, neurotic behaviors, disorganization of personality, and, occasionally, intellectual deterioration. Kayser-Fleischer rings, frequently present, result from copper deposition in Descemet's membrane of the cornea and reflect a high degree of copper storage in the body.
Last Evaluated: Feb 22, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:51946299
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 22, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:51946299
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 22, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:51946299
Benign/Likely benign
Hetero
Gene:
PLCG2
Variant:
c.770A>T
(p.His257Leu)
rsID: rs45443101
Ref Allele: A
Alt Allele: T
Freq: 2.5946%uncommon
CADD: 7.179
ClinVar Submissions (2)
Familial cold autoinflammatory syndrome-2 is an autosomal dominant immune disorder characterized by the development of cutaneous urticaria, erythema, and pruritus in response to cold exposure. Affected individuals have variable additional immunologic defects, including antibody deficiency, decreased numbers of B cells, defective B cells, increased susceptibility to infection, and increased risk of autoimmune disorders (summary by Ombrello et al., 2012). For a discussion of genetic heterogeneity of FCAS, see FCAS1 (120100).
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:81889176
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:81889176
Benign
Hetero
Gene:
DNAH8
Variant:
c.2620G>A
(p.Val874Met)
rsID: rs45529837
Ref Allele: G
Alt Allele: A
Freq: 2.6082%uncommon
CADD: 24
ClinVar Submissions (1)
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have "neonatal respiratory distress" requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:38789839
Benign
Hetero
Gene:
BRWD3
Variant:
c.*1036A>C
rsID: rs41300175
Ref Allele: T
Alt Allele: G
Freq: 2.6177%uncommon
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:80675573
Benign
Hetero
Gene:
RBCK1
Variant:
c.144G>A
(p.Glu48=)
rsID: rs41281892
Ref Allele: G
Alt Allele: A
Freq: 2.6225%uncommon
CADD: 9.25
ClinVar Submissions (1)
Polyglucosan body myopathy-1 is an autosomal recessive disorder characterized by onset in childhood of progressive proximal muscle weakness, resulting in difficulties in ambulation. Most patients also develop progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. A small subset of patients present with severe immunodeficiency and a hyperinflammatory state in very early childhood (summary by Boisson et al., 2012 and Nilsson et al., 2013). Genetic Heterogeneity of Polyglucosan Body Myopathy See also PGBM2 (616199), caused by mutation in the GYG1 gene (603942) on chromosome 3q24.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 20:410002
Benign
Hetero
Gene:
ANO5
Variant:
c.2521-13A>G
rsID: rs76850415
Ref Allele: A
Alt Allele: G
Freq: 2.6328%uncommon
CADD: 5.143
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 12, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:22279531
Benign
Hetero
Gene:
ATM
Variant:
c.8786+8A>C
rsID: rs4986839
Ref Allele: A
Alt Allele: C
Freq: 2.6328%uncommon
CADD: 5.249
ClinVar Submissions (11)
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 11
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108353888
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 11
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108353888
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 11
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108353888
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 11
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:108353888
Benign/Likely benign
Hetero
Gene:
MAGI2
Variant:
c.3915G>A
(p.Gln1305=)
rsID: rs117054456
Ref Allele: C
Alt Allele: T
Freq: 2.6551%uncommon
CADD: 16.4
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:78019768
Benign
Hetero
Gene:
MC2R
Variant:
c.*1604G>C
rsID: rs28926185
Ref Allele: C
Alt Allele: G
Freq: 2.6591%uncommon
CADD: 1.312
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:13883021
Likely benign
Hetero
Gene:
AP4B1
Variant:
c.402A>C
(p.Ser134=)
rsID: rs34751342
Ref Allele: T
Alt Allele: G
Freq: 2.6631%uncommon
CADD: 8.876
ClinVar Submissions (4)
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:113901822
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become non-ambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have global developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:113901822
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:113901822
Benign
Hetero
Gene:
CDHR1
Variant:
c.159C>A
(p.His53Gln)
rsID: rs12781048
Ref Allele: C
Alt Allele: A
Freq: 2.6679%uncommon
CADD: 0.003
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:84196512
Conflicting/Uncertain
Hetero
Gene:
CP
Variant:
c.2554+17G>A
rsID: rs35593818
Ref Allele: C
Alt Allele: T
Freq: 2.6966%uncommon
CADD: 0.206
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 17, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:149181988
Benign
Hetero
Gene:
GNPTAB
Variant:
c.3602+8C>A
rsID: rs79493678
Ref Allele: G
Alt Allele: T
Freq: 2.6989%uncommon
CADD: 0.892
ClinVar Submissions (5)
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101753364
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101753364
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101753364
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101753364
Benign/Likely benign
Hetero
Gene:
SLC13A5
Variant:
c.369-14C>T
rsID: rs218677
Ref Allele: G
Alt Allele: A
Freq: 2.7141%uncommon
CADD: 12.09
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 18, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:6704070
Benign
Hetero
Gene:
TSC2
Variant:
c.3883+78G>A
rsID: rs1800705
Ref Allele: G
Alt Allele: A
Freq: 2.7316%uncommon
CADD: 2.17
ClinVar Submissions (1)
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Last Evaluated: -
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 16:2082582
Hetero
Gene:
KIF1B
Variant:
c.*3154A>G
rsID: rs41310365
Ref Allele: A
Alt Allele: G
Freq: 2.7348%uncommon
CADD: 0.351
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:10379741
ALK-related neuroblastic tumor susceptibility is characterized by increased risk for neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is a more malignant tumor and ganglioneuroma a more benign tumor. Depending on the histologic findings, ganglioneuroblastoma can behave in a more aggressive fashion, like neuroblastoma, or in a benign fashion, like ganglioneuroma. Preliminary data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest an overall penetrance of approximately 57% with the risk for neuroblastic tumor development highest in infancy and decreasing by late childhood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:10379741
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:10379741
Likely benign
Hetero
Gene:
DNAH14
Variant:
c.2792C>A
(p.Ala931Asp)
rsID: rs115366080
Ref Allele: C
Alt Allele: A
Freq: 2.7459%uncommon
CADD: 0.162
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:225080404
Benign
Hetero
Gene:
COL4A2
Variant:
c.4195G>A
(p.Val1399Ile)
rsID: rs45520539
Ref Allele: G
Alt Allele: A
Freq: 2.7666%uncommon
CADD: 1.67
ClinVar Submissions (1)
A cavity within the cerebral hemisphere, filled with cerebrospinal fluid, that communicates directly with the ventricular system. [HPO:probinson, PMID:9279052]
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:110503903
Likely benign
Hetero
Gene:
SMAD9
Variant:
c.*2216G>A
rsID: rs117560648
Ref Allele: C
Alt Allele: T
Freq: 2.7754%uncommon
CADD: 0.569
ClinVar Submissions (1)
Pulmonary arterial hypertension (PAH) is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries. When a sufficient number of vessels are occluded, the resistance to blood flow through the lungs increases, and the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary blood flow. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure ensues. Initial symptoms include dyspnea (60%), fatigue (19%), syncope (8%), chest pain (7%), palpitations (5%), and leg edema (3%). All ages are affected, but the mean age at diagnosis is 36 years. Mean survival after diagnosis is 2.8 years; current therapy does improve clinical function but has modest effect on survival. The term "heritable PAH" (HPAH) includes familial PAH (PAH that occurs in two or more family members) and simplex PAH (i.e., a single occurrence in a family) when a pathogenic variant has been identified. Most heritable PAH (75%) is caused by a pathogenic variant in BMPR2; pathogenic variants in other genes (i.e., ACVRL1, KCNK3, CAV1, SMAD9, BMPR1B) are considerably less common (1%-3%). HPAH has identical symptoms, signs, and histology as PAH of unknown cause. The time from onset of symptoms to diagnosis may be shorter in individuals with familial PAH, possibly because of familial awareness of the disease. Three retrospective studies suggest that persons with PAH who have a BMPR2 pathogenic variant exhibit more severe disease.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:36846460
Likely benign
Homo
Gene:
KCNA5
Variant:
c.381C>T
(p.Ser127=)
rsID: rs45504599
Ref Allele: C
Alt Allele: T
Freq: 2.7818%uncommon
CADD: 0.033
ClinVar Submissions (2)
Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. The prevalence increases rapidly with age, to 2.3% between the ages of 40 and 60 years, and to 5.9% over the age of 65. The most dreaded complication is thromboembolic stroke (Brugada et al., 1997). For a discussion of genetic heterogeneity of atrial fibrillation, see 608583.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:5044528
Familial atrial fibrillation is an inherited abnormality of the heart's normal rhythm. Atrial fibrillation is characterized by episodes of uncoordinated electrical activity (fibrillation) in the heart's upper chambers (the atria), which cause a fast and irregular heartbeat. If untreated, this abnormal heart rhythm (arrhythmia) can lead to dizziness, chest pain, a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, or fainting (syncope). Atrial fibrillation also increases the risk of stroke and sudden death. Complications of atrial fibrillation can occur at any age, although some people with this heart condition never experience any health problems associated with the disorder.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:5044528
Benign/Likely benign
Hetero
Gene:
BCAM
Variant:
c.230G>A
(p.Arg77His)
rsID: rs28399653
Ref Allele: G
Alt Allele: A
Freq: 2.7961%uncommon
CADD: 3.799
ClinVar Submissions (1)
Last Evaluated: Dec 30, 2010
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:44812188
OMIM Allelic Variant: 612773.0001
Benign
Hetero
Gene:
POU4F3
Variant:
c.90C>T
(p.Ala30=)
rsID: rs28994879
Ref Allele: C
Alt Allele: T
Freq: 2.8264%uncommon
CADD: 15.38
ClinVar Submissions (4)
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:146339202
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:146339202
Benign/Likely benign
Hetero
Gene:
APC
Variant:
c.136-350A>G
rsID: rs78418904
Ref Allele: A
Alt Allele: G
Freq: 2.8319%uncommon
CADD: 4.817
ClinVar Submissions (1)
Colorectal cancer is a heterogeneous disease that is common in both men and women. In addition to lifestyle and environmental risk factors, gene defects can contribute to an inherited predisposition to CRC. CRC is caused by changes in different molecular pathogenic pathways, such as chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Chromosome instability is the most common alteration and is present in almost 85% of all cases (review by Schweiger et al., 2013). Genetic Heterogeneity of Colorectal Cancer Mutations in a single gene result in a marked predisposition to colorectal cancer in 2 distinct syndromes: familial adenomatous polyposis (FAP; 175100) and hereditary nonpolyposis colorectal cancer (HNPCC; see 120435). FAP is caused by mutations in the APC gene (611731), whereas HNPCC is caused by mutations in several genes, including MSH2 (609309), MLH1 (120436), PMS1 (600258), PMS2 (600259), MSH6 (600678), TGFBR2 (190182), and MLH3 (604395). Epigenetic silencing of MSH2 results in a form of HNPCC (see HNPCC8, 613244). Other colorectal cancer syndromes include autosomal recessive adenomatous polyposis (608456), which is caused by mutations in the MUTYH gene (604933), and oligodontia-colorectal cancer syndrome (608615), which is caused by mutations in the AXIN2 gene (604025). The CHEK2 gene (604373) has been implicated in susceptibility to colorectal cancer in Finnish patients. A germline mutation in the PLA2G2A gene (172411) was identified in a patient with colorectal cancer. Germline susceptibility loci for colorectal cancer have also been identified. CRCS1 (608812) is conferred by mutation in the GALNT12 gene (610290) on chromosome 9q22; CRCS2 (611469) maps to chromosome 8q24; CRCS3 (612229) is conferred by variation in the SMAD7 gene (602932) on chromosome 18; CRCS4 (601228) is conferred by variation on 15q that causes increased and ectopic expression of the GREM1 gene (603054); CRCS5 (612230) maps to chromosome 10p14; CRCS6 (612231) maps to chromosome 8q23; CRCS7 (612232) maps to chromosome 11q23; CRCS8 (612589) maps to chromosome 14q22; CRCS9 (612590) maps to 16q22; CRCS10 (612591) is conferred by mutation in the POLD1 gene (174761) on chromosome 19q13; CRCS11 (612592) maps to chromosome 20p12; and CRCS12 (615083) is conferred by mutation in the POLE gene (174762) on chromosome 12q24. Somatic mutations in many different genes, including KRAS (190070), PIK3CA (171834), BRAF (164757), CTNNB1 (116806), FGFR3 (134934), AXIN2 (604025), AKT1 (164730), MCC (159350), MYH11 (160745), PARK2 (602544), and RNF43 (612482), have been identified in colorectal cancer.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: other
Assembly: GRCh38
Chromosome/Position: 5:112765976
Hetero
Gene:
NDUFAF1
Variant:
c.-379C>T
rsID: rs146883891
Ref Allele: G
Alt Allele: A
Freq: 2.8606%uncommon
CADD: 6.611
ClinVar Submissions (1)
Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome (see 256000), Leber hereditary optic neuropathy (535000), and some forms of Parkinson disease (see 556500) (Loeffen et al., 2000; Pitkanen et al., 1996; Robinson, 1998). Genetic Heterogeneity of Complex I Deficiency Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible (summary by Haack et al., 2012). However, the majority of cases are caused by mutations in nuclear-encoded genes (Loeffen et al., 2000; Triepels et al., 2001). Complex I deficiency resulting from mutation in nuclear-encoded genes include MC1DN1, caused by mutation in the NDUFS4 gene (602694); MC1DN2 (618222), caused by mutation in the NDUFS8 gene (602141); MC1DN3 (618224), caused by mutation in the NDUFS7 gene (601825); MC1DN4 (618225), caused by mutation in the NDUFV1 gene (161015); MC1DN5 (618226), caused by mutation in the NDUFS1 gene (157655); MC1DN6 (618228), caused by mutation in the NDUFS2 gene (602985); MC1DN7 (618229), caused by mutation in the NDUFV2 gene (600532); MC1DN8 (618230), caused by mutation in the NDUFS3 gene (603846); MC1DN9 (618232), caused by mutation in the NDUFS6 gene (603848); MC1DN10 (618233), caused by mutation in the NDUFAF2 gene (609653); MC1DN11 (618234), caused by mutation in the NDUFAF1 gene (606934); MC1DN12 (301020), caused by mutation in the NDUFA1 gene (300078); MC1DN13 (618235), caused by mutation in the NDUFA2 gene (602137); MC1DN14 (618236), caused by mutation in the NDUFA11 gene (612638); MC1DN15 (618237), caused by mutation in the NDUFAF4 gene (611776); MC1DN16 (618238), caused by mutation in the NDUFAF5 gene (612360); MC1DN17 (618239), caused by mutation in the NDUFAF6 gene (612392); MC1DN18 (618240), caused by mutation in the NDUFAF3 gene (612911); MC1DN19 (618241), caused by mutation in the FOXRED1 gene (613622); MC1DN20 (611126), caused by mutation in the ACAD9 gene (611103); MC1DN21 (618242), caused by mutation in the NUBPL gene (613621); MC1DN22 (618243), caused by mutation in the NDUFA10 gene (603835); MC1DN23 (618244), caused by mutation in the NDUFA12 gene (614530); MC1DN24 (618245), caused by mutation in the NDUFB9 gene (601445); MC1DN25 (618246), caused by mutation in the NDUFB3 gene (603839); MC1DN26 (618247), caused by mutation in the NDUFA9 gene (603834); MC1DN27 (618248), caused by mutation in the MTFMT gene (611766); MC1DN28 (618249), caused by mutation in the NDUFA13 gene (609435); MC1DN29 (618250), caused by mutation in the TMEM126B gene (615533); MC1DN30 (301021), caused by mutation in the NDUFB11 gene (300403); MC1DN31 (618251), caused by mutation in the TIMMDC1 gene (615534); MC1DN32 (618252), caused by mutation in the NDUFB8 gene (602140); and MC1DN33 (618253), caused by mutation in the NDUFA6 gene (602138). Complex I deficiency with mitochondrial inheritance has been associated with mutation in 6 mitochondrial-encoded components of complex I: MTND1 (516000), MTND2 (516001), MTND3 (516002), MTND4 (516003), MTND5 (516005), MTND6 (516006). Most of these patients have a phenotype of Leber hereditary optic neuropathy (LHON; 535000) or Leigh syndrome. Features of complex I deficiency may also be caused by mutation in other mitochondrial genes, including MTTS2 (590085).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:41402441
Conflicting/Uncertain
Hetero
Gene:
FANCE
Variant:
c.1071C>T
(p.Leu357=)
rsID: rs3823434
Ref Allele: C
Alt Allele: T
Freq: 2.8622%uncommon
CADD: 8.313
ClinVar Submissions (3)
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:35458398
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:35458398
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:35458398
Benign/Likely benign
Hetero
Gene:
ACADS
Variant:
c.511C>T
(p.Arg171Trp)
rsID: rs1800556
Ref Allele: C
Alt Allele: T
Freq: 2.8686%uncommon
CADD: 22
ClinVar Submissions (7)
Most infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria are reported. Thus, SCADD is now viewed as a biochemical phenotype rather than a disease. A broad range of clinical findings was originally reported in those with confirmed SCADD, including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported. In a large series of affected individuals detected on metabolic evaluation for developmental delay, 20% had failure to thrive, feeding difficulties, and hypotonia; 22% had seizures; and 30% had hypotonia without seizures. In contrast, the majority of infants with SCADD have been detected by expanded newborn screening, and the great majority of these infants remain asymptomatic. As with other fatty acid oxidation deficiencies, characteristic biochemical findings of SCADD may be absent except during times of physiologic stress such as fasting and illness. A diagnosis of SCADD based on clinical findings should not preclude additional testing to look for other causes.
Last Evaluated: Jun 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 12:120737875
OMIM Allelic Variant: 606885.0006
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 12:120737875
OMIM Allelic Variant: 606885.0006
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 28, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 12:120737875
OMIM Allelic Variant: 606885.0006
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
FPR1
Variant:
c.306T>C
(p.Phe102=)
rsID: rs28930680
Ref Allele: A
Alt Allele: G
Freq: 2.8702%uncommon
CADD: 0.985
ClinVar Submissions (1)
An acute or chronic inflammatory process that affects the tissues that surround and support the teeth.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:51746689
Benign
Hetero
Gene:
TAF1
Variant:
c.868C>G
(p.Leu290Val)
rsID: rs28382158
Ref Allele: C
Alt Allele: G
Freq: 2.8789%uncommon
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 13, 2013
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:71377696
Benign
Hetero
Gene:
SYCP3
Variant:
c.-118T>A
rsID: rs17031944
Ref Allele: A
Alt Allele: T
Freq: 2.8885%uncommon
CADD: 6.276
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101739455
Likely benign
Hetero
Gene:
IL36RN
Variant:
c.*935G>C
rsID: rs11675540
Ref Allele: G
Alt Allele: C
Freq: 2.8917%uncommon
CADD: 6.278
ClinVar Submissions (1)
Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein (123260) (summary by Marrakchi et al., 2011). GPP often presents in patients with existing or prior psoriasis vulgaris (PV; see 177900); however, GPP can develop without a history of PV (Sugiura et al., 2013). Palmoplantar pustulosis and acrodermatitis continua of Hallopeau represent acral forms of pustular psoriasis that have historically been grouped with GPP (summary by Setta-Kaffetzi et al., 2013). GPP in association with sterile multifocal osteomyelitis and periostitis (612852) is caused by mutation in the IL1RN gene (147679). Capon (2013) noted that the percentage of GPP patients reported to be negative for mutation in IL36RN ranges from 51 to 84%, indicative of genetic heterogeneity in the generalized pustular form of psoriasis. For a discussion of genetic heterogeneity of psoriasis, see PSORS1 (177900).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:113063612
Likely benign
Hetero
Gene:
GNPTAB
Variant:
c.204-15G>T
rsID: rs10860787
Ref Allele: C
Alt Allele: A
Freq: 2.8925%uncommon
CADD: 0.534
ClinVar Submissions (3)
Last Evaluated: Dec 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:101790072
Last Evaluated: Dec 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:101790072
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:101790072
Benign
Hetero
Gene:
MYH14
Variant:
c.474T>C
(p.Ile158=)
rsID: rs34796700
Ref Allele: T
Alt Allele: C
Freq: 2.9004%uncommon
CADD: 6.867
ClinVar Submissions (4)
Last Evaluated: Dec 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:50217683
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:50217683
Benign/Likely benign
Hetero
Gene:
ACHE
Variant:
c.1057C>A
(p.His353Asn)
rsID: rs1799805
Ref Allele: G
Alt Allele: T
Freq: 2.9203%uncommon
CADD: 16.73
ClinVar Submissions (1)
Last Evaluated: May 01, 1993
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:100893176
OMIM Allelic Variant: 100740.0001
Benign
Hetero
Gene:
COG5
Variant:
c.1920C>T
(p.Ile640=)
rsID: rs35581984
Ref Allele: G
Alt Allele: A
Freq: 2.9442%uncommon
CADD: 6.58
ClinVar Submissions (3)
A genetically heterogeneous group of heritable disorders resulting from defects in protein N-glycosylation.
Last Evaluated: Jul 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:107248422
COG5-congenital disorder of glycosylation (COG5-CDG, formerly known as congenital disorder of glycosylation type IIi) is an inherited condition that causes neurological problems and other abnormalities. The pattern and severity of this disorder's signs and symptoms vary among affected individuals.Individuals with COG5-CDG typically develop signs and symptoms of the condition during infancy. These individuals often have weak muscle tone (hypotonia) and delayed development. Other neurological features include moderate to severe intellectual disability, poor coordination, and difficulty walking. Some affected individuals never learn to speak. Other features of COG5-CDG include short stature, an unusually small head size (microcephaly), and distinctive facial features, which can include ears that are set low and rotated backward, a short neck with a low hairline in the back, and a prominent nose. Less commonly, affected individuals can have hearing loss caused by changes in the inner ear (sensorineural hearing loss), vision impairment, damage to the nerves that control bladder function (a condition called neurogenic bladder), liver disease, and joint deformities (contractures).
Last Evaluated: Jul 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:107248422
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:107248422
Benign/Likely benign
Hetero
Gene:
PLCG2
Variant:
c.2054+7G>A
rsID: rs138158454
Ref Allele: G
Alt Allele: A
Freq: 2.9506%uncommon
CADD: 2.985
ClinVar Submissions (1)
Familial cold autoinflammatory syndrome-2 is an autosomal dominant immune disorder characterized by the development of cutaneous urticaria, erythema, and pruritus in response to cold exposure. Affected individuals have variable additional immunologic defects, including antibody deficiency, decreased numbers of B cells, defective B cells, increased susceptibility to infection, and increased risk of autoimmune disorders (summary by Ombrello et al., 2012). For a discussion of genetic heterogeneity of FCAS, see FCAS1 (120100).
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:81912723
Benign
Hetero
Gene:
CRTAP
Variant:
c.*269C>T
rsID: rs143237314
Ref Allele: C
Alt Allele: T
Freq: 2.9554%uncommon
CADD: 1.352
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:33142717
Conflicting/Uncertain
Hetero
Gene:
ASXL1
Variant:
c.*548G>C
rsID: rs41289852
Ref Allele: G
Alt Allele: C
Freq: 2.9673%uncommon
CADD: 11.45
ClinVar Submissions (1)
Bohring-Opitz syndrome (BOS) is characterized by distinctive facial features and posture, growth failure, variable but usually severe intellectual disability, and variable anomalies. The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex), prominent globes, widely set eyes, palate anomalies, and micrognathia. The BOS posture, which is most striking in early childhood and often becomes less apparent with age, is characterized by flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints. Feeding difficulties in early childhood, including cyclic vomiting, have a significant impact on overall health; feeding tends to improve with age. Seizures are common and typically responsive to standard epileptic medications. Minor cardiac anomalies and transient bradycardia and apnea may be present. Affected individuals may experience recurrent infections, which also tend to improve with age. Isolated case reports suggest that individuals with BOS are at greater risk for Wilms tumor than the general population, but large-scale epidemiologic studies have not been conducted.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 20:32437886
Likely benign
Hetero
Gene:
ITGA9
Variant:
c.2667+32G>A
rsID: rs76424398
Ref Allele: G
Alt Allele: A
Freq: 2.9745%uncommon
CADD: 3.68
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 02, 2012
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:37777549
Benign
Hetero
Gene:
GLI3
Variant:
c.*265A>C
rsID: rs201493390
Ref Allele: T
Alt Allele: G
Freq: 3.0223%uncommon
CADD: 7.597
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:41964065
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:41964065
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:41964065
Conflicting/Uncertain
Hetero
Gene:
MYO1C
Variant:
c.1377+9T>G
rsID: rs2286877
Ref Allele: A
Alt Allele: C
Freq: 3.0462%uncommon
CADD: 10.84
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 22, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:1477882
Benign
Hetero
Gene:
ROBO3
Variant:
c.1267G>A
(p.Val423Met)
rsID: rs4935898
Ref Allele: G
Alt Allele: A
Freq: 3.0629%uncommon
CADD: 23.5
ClinVar Submissions (1)
HGPPS is an autosomal recessive neurologic disorder characterized by eye movement abnormalities apparent from birth and childhood-onset progressive scoliosis. These features are associated with a developmental malformation of the brainstem including hypoplasia of the pons and cerebellar peduncles and defective decussation of certain neuronal systems. Cognitive function is normal (summary by Bosley et al., 2005). Genetic Heterogeneity of Familial Horizontal Gaze Palsy With Progressive Scoliosis See also HGPPS2 (617542), caused by mutation in the DCC gene (120470) on chromosome 18q21.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:124872489
Likely benign
Hetero
Gene:
CCDC50
Variant:
c.363A>T
(p.Leu121Phe)
rsID: rs35380043
Ref Allele: A
Alt Allele: T
Freq: 3.0669%uncommon
CADD: 24
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:191369951
Benign
Hetero
Gene:
TUBB
Variant:
c.651G>A
(p.Leu217=)
rsID: rs25497
Ref Allele: G
Alt Allele: A
Freq: 3.0677%uncommon
CADD: 15.54
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 02, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:30723713
Benign
Hetero
Gene:
FBN2
Variant:
c.1231+37C>G
rsID: rs28763953
Ref Allele: G
Alt Allele: C
Freq: 3.0709%uncommon
CADD: 0.005
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:128395085
Likely benign
Hetero
Gene:
TP63
Variant:
c.1652+46G>A
rsID: rs35558939
Ref Allele: G
Alt Allele: A
Freq: 3.1178%uncommon
CADD: 1.787
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:189889530
Likely benign
Hetero
Gene:
COMP
Variant:
c.1156A>G
(p.Asn386Asp)
rsID: rs61739916
Ref Allele: T
Alt Allele: C
Freq: 3.164%uncommon
CADD: 26
ClinVar Submissions (3)
Autosomal dominant multiple epiphyseal dysplasia (MED) presents in early childhood, usually with pain in the hips and/or knees after exercise. Affected children complain of fatigue with long-distance walking. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:18786630
Autosomal dominant multiple epiphyseal dysplasia (MED) presents in early childhood, usually with pain in the hips and/or knees after exercise. Affected children complain of fatigue with long-distance walking. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:18786630
Pseudoachondroplasia is characterized by normal length at birth and normal facies. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, the growth rate falls below the standard growth curve by approximately age two years, leading to a moderately severe form of disproportionate short-limb short stature. Joint pain during childhood, particularly in the large joints of the lower extremities, is common. Degenerative joint disease is progressive; approximately 50% of individuals with pseudoachondroplasia eventually require hip replacement surgery.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:18786630
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:18786630
Benign/Likely benign
Hetero
Gene:
SPATA5
Variant:
c.1918G>C
(p.Glu640Gln)
rsID: rs35343500
Ref Allele: G
Alt Allele: C
Freq: 3.1704%uncommon
CADD: 15.17
ClinVar Submissions (1)
Epilepsy, hearing loss, and mental retardation syndrome is an autosomal recessive disorder characterized by severe neurologic impairment including intellectual disability, intractable epilepsy, microcephaly, abnormal muscle tone, and sensorineural hearing loss. Most affected individuals are nonambulatory, cannot sit unassisted, and have no speech development. More variable features include feeding difficulties, poor growth, cortical visual impairment, spasticity, scoliosis, immunodeficiency, and thrombocytopenia (summary by Tanaka et al., 2015).
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:123028234
Benign
Hetero
Gene:
ADAMTSL2
Variant:
c.2142G>A
(p.Ser714=)
rsID: rs11542920
Ref Allele: G
Alt Allele: A
Freq: 3.172%uncommon
CADD: 0.917
ClinVar Submissions (1)
A syndrome characterized by a smiling or happy facial expression (hence the adjective "geleophysic" from Greek gelios, laughing + physis, nature), short stature, brachydactyly, and dysostosis multiplex-like changes in the hands and feet. Infiltration of heart valves and liver with mucopolysaccharide-like substance has been demonstrated in some patients. Mild developmental delay is associated in some cases, but speech retardation may be attributed to hearing problems. Psychomotor retardation is an occasional feature.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:133568656
Conflicting/Uncertain
Homo
Gene:
GPC6
Variant:
c.*4182C>A
rsID: rs41275874
Ref Allele: C
Alt Allele: A
Freq: 3.176%uncommon
CADD: 13.81
ClinVar Submissions (1)
Omodysplasia is a rare skeletal dysplasia characterised by severe limb shortening and facial dysmorphism. Two types of omodysplasia have been described: an autosomal recessive or generalised form (also referred to as micromelic dysplasia with dislocation of radius) marked by severe micromelic dwarfism with predominantly rhizomelic shortening of both the upper and lower limbs, and an autosomal dominant form in which stature is normal and shortening is limited to the upper limbs. In total, less than 40 cases of omodysplasia have been described in the literature so far, with the majority of reported cases concerning the autosomal recessive form of the disease. The aetiology remains unknown but a paternally inherited paracentric inversion of 15q13 to q21.3 has been detected in one family.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:94407399
Likely benign
Hetero
Gene:
QDPR
Variant:
c.255C>T
(p.Cys85=)
rsID: rs12645938
Ref Allele: G
Alt Allele: A
Freq: 3.1808%uncommon
CADD: 16.61
ClinVar Submissions (2)
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:17504419
Tetrahydrobiopterin deficiency is a rare disorder characterized by a shortage (deficiency) of a molecule called tetrahydrobiopterin or BH4. This condition alters the levels of several substances in the body, including phenylalanine. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in foods that contain protein and in some artificial sweeteners. High levels of phenylalanine are present from early infancy in people with untreated tetrahydrobiopterin deficiency. This condition also alters the levels of chemicals called neurotransmitters, which transmit signals between nerve cells in the brain.Infants with tetrahydrobiopterin deficiency appear normal at birth, but medical problems ranging from mild to severe become apparent over time. Signs and symptoms of this condition can include intellectual disability, progressive problems with development, movement disorders, difficulty swallowing, seizures, behavioral problems, and an inability to control body temperature.
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:17504419
Benign/Likely benign
Hetero
Gene:
MALT1
Variant:
c.-84G>A
rsID: rs56142402
Ref Allele: G
Alt Allele: A
Freq: 3.1967%uncommon
CADD: 14.57
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:58671560
Benign
Hetero
Gene:
ADAMTSL2
Variant:
c.2325C>G
(p.Ser775=)
rsID: rs2301606
Ref Allele: C
Alt Allele: G
Freq: 3.2054%uncommon
CADD: 8.753
ClinVar Submissions (1)
A syndrome characterized by a smiling or happy facial expression (hence the adjective "geleophysic" from Greek gelios, laughing + physis, nature), short stature, brachydactyly, and dysostosis multiplex-like changes in the hands and feet. Infiltration of heart valves and liver with mucopolysaccharide-like substance has been demonstrated in some patients. Mild developmental delay is associated in some cases, but speech retardation may be attributed to hearing problems. Psychomotor retardation is an occasional feature.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:133569488
Conflicting/Uncertain
Homo
Gene:
PNPLA6
Variant:
c.2433G>A
(p.Ser811=)
rsID: rs522776
Ref Allele: G
Alt Allele: A
Freq: 3.2174%uncommon
CADD: 1.478
ClinVar Submissions (2)
PNPLA6-related disorders span a phenotypic continuum characterized by variable combinations of cerebellar ataxia, upper motor neuron involvement manifesting as spasticity and/or brisk reflexes, chorioretinal dystrophy associated with variable degrees of reduced visual function, and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics), either in isolation or as part of anterior hypopituitarism (growth hormone, thyroid hormone, or gonadotropin deficiencies). Common but less frequent features are peripheral neuropathy (usually of axonal type manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting), hair anomalies (long eyelashes, bushy eyebrows, or scalp alopecia), short stature, and impaired cognitive functioning (learning disabilities in children and deficits in attention, visuospatial abilities, and recall in adults). Some of these features can occur in distinct clusters on the phenotypic continuum: Boucher-Neuhäuser syndrome (cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism); Gordon Holmes syndrome (cerebellar ataxia, hypogonadotropic hypogonadism, and – to a variable degree – brisk reflexes); Oliver-McFarlane syndrome (trichomegaly, chorioretinal dystrophy, short stature, intellectual disability, and hypopituitarism); Laurence-Moon syndrome; and spastic paraplegia type 39 (SPG39) (upper motor neuron involvement, peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia).
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7554636
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7554636
Benign
Hetero
Gene:
SZT2
Variant:
c.5214T>G
(p.Ser1738=)
rsID: rs12129487
Ref Allele: T
Alt Allele: G
Freq: 3.2293%uncommon
CADD: 6.604
ClinVar Submissions (3)
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Last Evaluated: Jan 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:43432382
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:43432382
Benign
Hetero
Gene:
PRPF3
Variant:
c.*228A>G
rsID: rs41300863
Ref Allele: A
Alt Allele: G
Freq: 3.2389%uncommon
CADD: 16.69
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:150353207
Likely benign
Hetero
Gene:
APC
Variant:
c.423-666G>A
rsID: rs74639338
Ref Allele: G
Alt Allele: A
Freq: 3.2461%uncommon
CADD: 1.05
ClinVar Submissions (1)
Colorectal cancer is a heterogeneous disease that is common in both men and women. In addition to lifestyle and environmental risk factors, gene defects can contribute to an inherited predisposition to CRC. CRC is caused by changes in different molecular pathogenic pathways, such as chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Chromosome instability is the most common alteration and is present in almost 85% of all cases (review by Schweiger et al., 2013). Genetic Heterogeneity of Colorectal Cancer Mutations in a single gene result in a marked predisposition to colorectal cancer in 2 distinct syndromes: familial adenomatous polyposis (FAP; 175100) and hereditary nonpolyposis colorectal cancer (HNPCC; see 120435). FAP is caused by mutations in the APC gene (611731), whereas HNPCC is caused by mutations in several genes, including MSH2 (609309), MLH1 (120436), PMS1 (600258), PMS2 (600259), MSH6 (600678), TGFBR2 (190182), and MLH3 (604395). Epigenetic silencing of MSH2 results in a form of HNPCC (see HNPCC8, 613244). Other colorectal cancer syndromes include autosomal recessive adenomatous polyposis (608456), which is caused by mutations in the MUTYH gene (604933), and oligodontia-colorectal cancer syndrome (608615), which is caused by mutations in the AXIN2 gene (604025). The CHEK2 gene (604373) has been implicated in susceptibility to colorectal cancer in Finnish patients. A germline mutation in the PLA2G2A gene (172411) was identified in a patient with colorectal cancer. Germline susceptibility loci for colorectal cancer have also been identified. CRCS1 (608812) is conferred by mutation in the GALNT12 gene (610290) on chromosome 9q22; CRCS2 (611469) maps to chromosome 8q24; CRCS3 (612229) is conferred by variation in the SMAD7 gene (602932) on chromosome 18; CRCS4 (601228) is conferred by variation on 15q that causes increased and ectopic expression of the GREM1 gene (603054); CRCS5 (612230) maps to chromosome 10p14; CRCS6 (612231) maps to chromosome 8q23; CRCS7 (612232) maps to chromosome 11q23; CRCS8 (612589) maps to chromosome 14q22; CRCS9 (612590) maps to 16q22; CRCS10 (612591) is conferred by mutation in the POLD1 gene (174761) on chromosome 19q13; CRCS11 (612592) maps to chromosome 20p12; and CRCS12 (615083) is conferred by mutation in the POLE gene (174762) on chromosome 12q24. Somatic mutations in many different genes, including KRAS (190070), PIK3CA (171834), BRAF (164757), CTNNB1 (116806), FGFR3 (134934), AXIN2 (604025), AKT1 (164730), MCC (159350), MYH11 (160745), PARK2 (602544), and RNF43 (612482), have been identified in colorectal cancer.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: other
Assembly: GRCh38
Chromosome/Position: 5:112774963
Hetero
Gene:
CNTN1
Variant:
c.1956A>G
(p.Ala652=)
rsID: rs2229930
Ref Allele: A
Alt Allele: G
Freq: 3.2739%uncommon
CADD: 6.45
ClinVar Submissions (4)
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:40981060
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:40981060
Benign
Hetero
Gene:
ARHGEF28
Variant:
c.4388G>A
(p.Arg1463Gln)
rsID: rs17634853
Ref Allele: G
Alt Allele: A
Freq: 3.3233%uncommon
CADD: 23.2
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:73909638
Benign
Hetero
Gene:
CDON
Variant:
c.*3862G>T
rsID: rs73019367
Ref Allele: C
Alt Allele: A
Freq: 3.3265%uncommon
CADD: 1.365
ClinVar Submissions (1)
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:125957080
Likely benign
Hetero
Gene:
TMPRSS3
Variant:
c.268G>A
(p.Ala90Thr)
rsID: rs45598239
Ref Allele: C
Alt Allele: T
Freq: 3.3329%uncommon
CADD: 22.4
ClinVar Submissions (5)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 21:42388983
Benign
Hetero
Gene:
LEP
Variant:
c.*366A>T
rsID: rs28954118
Ref Allele: A
Alt Allele: T
Freq: 3.3408%uncommon
CADD: 2.092
ClinVar Submissions (1)
Congenital leptin deficiency is a condition that causes severe obesity beginning in the first few months of life. Affected individuals are of normal weight at birth, but they are constantly hungry and quickly gain weight. Without treatment, the extreme hunger continues and leads to chronic excessive eating (hyperphagia) and obesity. Beginning in early childhood, affected individuals develop abnormal eating behaviors such as fighting with other children over food, hoarding food, and eating in secret.People with congenital leptin deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production of hormones that direct sexual development. Without treatment, affected individuals experience delayed puberty or do not go through puberty, and may be unable to conceive children (infertile).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:128255129
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:128255129
Conflicting/Uncertain
Hetero
Gene:
CD40
Variant:
c.*135C>G
rsID: rs11569343
Ref Allele: C
Alt Allele: G
Freq: 3.3432%uncommon
CADD: 3.631
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 20:46129175
Likely benign
Hetero
Gene:
GLI3
Variant:
c.*847C>A
rsID: rs116986447
Ref Allele: G
Alt Allele: T
Freq: 3.3448%uncommon
CADD: 0.392
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963483
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963483
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963483
Likely benign
Hetero
Gene:
GLI3
Variant:
c.*1087A>T
rsID: rs76023240
Ref Allele: T
Alt Allele: A
Freq: 3.3472%uncommon
CADD: 0.456
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963243
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963243
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963243
Likely benign
Hetero
Gene:
GLI3
Variant:
c.4609C>T
(p.Arg1537Cys)
rsID: rs35364414
Ref Allele: G
Alt Allele: A
Freq: 3.3488%uncommon
CADD: 34
ClinVar Submissions (3)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964464
Benign/Likely benign
Hetero
Gene:
GLI3
Variant:
c.4020C>T
(p.Pro1340=)
rsID: rs35139358
Ref Allele: G
Alt Allele: A
Freq: 3.3504%uncommon
CADD: 0.228
ClinVar Submissions (3)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965053
Benign/Likely benign
Hetero
Gene:
GLI3
Variant:
c.4007G>A
(p.Gly1336Glu)
rsID: rs35280470
Ref Allele: C
Alt Allele: T
Freq: 3.3504%uncommon
CADD: 11.47
ClinVar Submissions (3)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41965066
Benign/Likely benign
Hetero
Gene:
TTN
Variant:
c.30683-2del1
rsID: rs1553868981
Ref Allele: T
Alt Allele: TA
Freq: 3.3512%uncommon
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 16, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:178698916
Benign
Hetero
Gene:
ARHGEF28
Variant:
c.4642C>T
(p.Pro1548Ser)
rsID: rs17634865
Ref Allele: C
Alt Allele: T
Freq: 3.3719%uncommon
CADD: 0.003
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:73909892
Benign
Hetero
Gene:
SPINK5
Variant:
c.316G>A
(p.Asp106Asn)
rsID: rs17860502
Ref Allele: G
Alt Allele: A
Freq: 3.3846%uncommon
CADD: 0.279
ClinVar Submissions (3)
Netherton syndrome is a rare and severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Generalized scaly erythroderma is apparent at or soon after birth and usually persists. Scalp hair is sparse and brittle with a characteristic 'bamboo' shape under light microscopic examination due to invagination of the distal part of the hair shaft to its proximal part. Atopic manifestations include eczema-like rashes, atopic dermatitis, pruritus, hay fever, angioedema, urticaria, high levels of IgE in the serum, and hypereosinophilia. Life-threatening complications are frequent during the neonatal period, including hypernatremic dehydration, hypothermia, extreme weight loss, bronchopneumonia, and sepsis. During childhood, failure to thrive is common as a result of malnutrition, metabolic disorders, chronic erythroderma, persistent cutaneous infections, or enteropathy (summary by Bitoun et al., 2002).
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:148086438
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:148086438
Benign/Likely benign
Hetero
Gene:
GLI3
Variant:
c.*30G>T
rsID: rs77886553
Ref Allele: C
Alt Allele: A
Freq: 3.3846%uncommon
CADD: 0.253
ClinVar Submissions (2)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964300
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964300
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964300
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964300
Benign/Likely benign
Hetero
Gene:
GLI3
Variant:
c.*655A>G
rsID: rs77197280
Ref Allele: T
Alt Allele: C
Freq: 3.3854%uncommon
CADD: 1.053
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963675
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963675
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963675
Likely benign
Hetero
Gene:
GLI3
Variant:
c.*136T>A
rsID: rs78794712
Ref Allele: A
Alt Allele: T
Freq: 3.3854%uncommon
CADD: 9.772
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964194
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964194
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41964194
Likely benign
Hetero
Gene:
GLI3
Variant:
c.*726A>G
rsID: rs118157739
Ref Allele: T
Alt Allele: C
Freq: 3.3918%uncommon
CADD: 0.103
ClinVar Submissions (1)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963604
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963604
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41963604
Likely benign
Hetero
Gene:
GLI3
Variant:
c.2826G>C
(p.Pro942=)
rsID: rs34245321
Ref Allele: C
Alt Allele: G
Freq: 3.3958%uncommon
CADD: 6.879
ClinVar Submissions (4)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41966247
Benign/Likely benign
Hetero
Gene:
TTN
Variant:
c.14744G>A
(p.Arg4915His)
rsID: rs72648907
Ref Allele: C
Alt Allele: T
Freq: 3.4651%uncommon
CADD: 1.8
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 20, 2013
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:178747656
Benign
Hetero
Gene:
NME8
Variant:
c.1013T>C
(p.Ile338Thr)
rsID: rs62001870
Ref Allele: T
Alt Allele: C
Freq: 3.4762%uncommon
CADD: 24.2
ClinVar Submissions (3)
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have "neonatal respiratory distress" requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:37884321
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:37884321
Low clinical importance, Uncertain benign — Tentatively classified as benign, but predicted to be damaging and other variants in this gene are implicated in causing primary ciliary dyskinesia (situs inversus, chronic sinusitis, and bronchiectasis).
Benign
Hetero
Gene:
ORC4
Variant:
c.166C>G
(p.Leu56Val)
rsID: rs2307397
Ref Allele: G
Alt Allele: C
Freq: 3.485%uncommon
CADD: 10.27
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:147972798
Benign
Hetero
Gene:
HNF4A
Variant:
c.201C>T
(p.Ala67=)
rsID: rs736823
Ref Allele: C
Alt Allele: T
Freq: 3.4993%uncommon
CADD: 21.4
ClinVar Submissions (5)
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 20:44406143
Maturity-onset diabetes of the young is an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but represents genetic, metabolic, and clinical heterogeneity (Vaxillaire and Froguel, 2008). Genetic Heterogeneity of MODY MODY1 (125850) is caused by heterozygous mutation in the hepatocyte nuclear factor-4-alpha gene (HNF4A; 600281) on chromosome 20. MODY2 (125851) is caused by heterozygous mutation in the glucokinase gene (GCK; 138079) on chromosome 7. MODY3 (600496) is caused by heterozygous mutation in the hepatocyte nuclear factor-1alpha gene (HNF1A; 142410) on chromosome 12q24.2. MODY4 (606392) is caused by heterozygous mutation in the pancreas/duodenum homeobox protein-1 gene (PDX1; 600733) on chromosome 13q12.1. MODY5 (137920) is caused by heterozygous mutation in the gene encoding hepatic transcription factor-2 (TCF2; 189907) on chromosome 17cen-q21.3. MODY6 (606394) is caused by heterozygous mutation in the NEUROD1 gene (601724) on chromosome 2q32. MODY7 (610508) is caused by heterozygous mutation in the KLF11 gene (603301) on chromosome 2p25. MODY8 (609812), or diabetes-pancreatic exocrine dysfunction syndrome, is caused by heterozygous mutation in the CEL gene (114840) on chromosome 9q34. MODY9 (612225) is caused by heterozygous mutation in the PAX4 gene (167413) on chromosome 7q32. MODY10 (613370) is caused by heterozygous mutation in the insulin gene (INS; 176730) on chromosome 11p15.5. MODY11 (613375) is caused by heterozygous mutation in the BLK gene (191305) on chromosome 8p23. MODY13 (616329) is caused by heterozygous mutation in the KCNJ11 gene (600937) on chromosome 11p15. MODY14 (616511) is caused by heterozygous mutation in the APPL1 gene (604299) on chromosome 3p14.
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 20:44406143
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 20:44406143
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 20:44406143
Benign/Likely benign
Hetero
Gene:
KBTBD13
Variant:
c.*846G>T
rsID: rs17804968
Ref Allele: G
Alt Allele: T
Freq: 3.5049%uncommon
CADD: 1.515
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:65079038
Likely benign
Hetero
Gene:
FZD4
Variant:
c.*4765T>C
rsID: rs72963441
Ref Allele: A
Alt Allele: G
Freq: 3.5144%uncommon
CADD: 17.27
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:86946377
Likely benign
Hetero
Gene:
HEPACAM
Variant:
c.339G>A
(p.Gln113=)
rsID: rs74570840
Ref Allele: C
Alt Allele: T
Freq: 3.5256%uncommon
CADD: 19.31
ClinVar Submissions (2)
The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by early-onset macrocephaly, often in combination with mild gross motor developmental delay and seizures; gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings; and usually late onset of mild mental deterioration. Macrocephaly, observed in virtually all individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable and can be as great as 4 to 6 SD above the mean in some individuals. After the first year of life, head growth rate normalizes and growth follows a line parallel to and usually several centimeters above the 98th centile. Initial mental and motor development is normal in most individuals. Walking is often unstable, followed by ataxia of the trunk and extremities, then minor signs of pyramidal dysfunction and brisk deep-tendon stretch reflexes. Almost all individuals have epilepsy from an early age. The epilepsy is typically well controlled with medication, but status epilepticus occurs relatively frequently. Mental deterioration is late and mild. Disease severity ranges from independent walking for a few years only to independent walking in the fifth decade. Some individuals have died in their teens or twenties; others are alive in their fifties. An improving phenotype has a similar initial presentation with delayed mental or motor development, followed by an improving clinical course: macrocephaly usually persists, but some children become normocephalic; motor function improves or normalizes; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some have intellectual disability that is stable, with or without autism. Epilepsy and status epilepticus may occur.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:124924816
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:124924816
Benign/Likely benign
Hetero
Gene:
ARHGEF28
Variant:
c.4622C>G
(p.Ala1541Gly)
rsID: rs78992879
Ref Allele: C
Alt Allele: G
Freq: 3.6339%uncommon
CADD: 7.712
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:73909872
Benign
Hetero
Gene:
GNB4
Variant:
c.48T>C
(p.Asn16=)
rsID: rs1078749
Ref Allele: A
Alt Allele: G
Freq: 3.6427%uncommon
CADD: 10.54
ClinVar Submissions (1)
CMTDIF is an autosomal dominant neurologic disorder characterized by onset around adolescence of slowly progressive distal muscle atrophy and weakness affecting the upper and lower limbs and resulting in steppage gait. There is distal sensory impairment with decreased reflexes. Nerve conduction velocities are variable, ranging from the demyelinating to the axonal range (summary by Soong et al., 2013). For a discussion of genetic heterogeneity of CMTDI, see 606482.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:179426153
Benign
Hetero
Gene:
CYP1B1
Variant:
c.*1871C>T
rsID: rs9341266
Ref Allele: G
Alt Allele: A
Freq: 3.6442%uncommon
CADD: 8.911
ClinVar Submissions (1)
Anterior segment dysgeneses (ASGD or ASMD) are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (summary by Cheong et al., 2016). Anterior segment dysgenesis is sometimes divided into subtypes including aniridia (see 106210), Axenfeld and Rieger anomalies, iridogoniodysgenesis, Peters anomaly, and posterior embryotoxon (Gould and John, 2002). Patients with ASGD5 have been reported with the Peters anomaly, Axenfeld anomaly, and Rieger anomaly subtypes. Peters anomaly consists of a central corneal leukoma, absence of the posterior corneal stroma and Descemet membrane, and a variable degree of iris and lenticular attachments to the central aspect of the posterior cornea (Peters, 1906). It occurs as an isolated ocular abnormality or in association with other ocular defects. In Axenfeld anomaly, strands of iris tissue attach to the Schwalbe line; in Rieger anomaly, in addition to the attachment of iris tissue to the Schwalbe line, there is clinically evident iris stromal atrophy with hole or pseudo-hole formation and corectopia (summary by Smith and Traboulsi, 2012).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:38068851
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:38068851
Likely benign
Hetero
Gene:
TULP1
Variant:
c.1362G>A
(p.Thr454=)
rsID: rs41270076
Ref Allele: C
Alt Allele: T
Freq: 3.6562%uncommon
CADD: 0.597
ClinVar Submissions (2)
Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). Genetic Heterogeneity of Leber Congenital Amaurosis LCA2 (204100) is caused by mutation in the RPE65 gene (RPE65; 180069) on chromosome 1p31. LCA3 (604232) is caused by mutation in the SPATA7 gene (609868) on chromosome 14q31. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14. LCA6 (613826) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. LCA7 (613829) is caused by mutation in the CRX gene (602225) on chromosome 19q13. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31. LCA9 (608553) is caused by mutation in the NMNAT1 gene (608700) on chromosome 1p36. LCA10 (611755) is caused by mutation in the CEP290 gene (610142) on chromosome 12q21 and may account for as many as 21% of cases of LCA. LCA11 (613837) is caused by mutation in the IMPDH1 gene (146690) on chromosome 7q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q32. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. LCA17 (615360) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. LCA18 (see 608133) is caused by mutation in the PRPH2 gene (179605) on chromosome 6p21. Perrault et al. (1999) provided a review of Leber congenital amaurosis, with emphasis on genetic heterogeneity. Wiszniewski et al. (2011) analyzed 13 known LCA genes in 60 LCA probands, and identified homozygous or compound heterozygous mutations in 42 (70%). In addition, a third disease-associated mutant allele at a second locus was identified in 7 (12%) of the 60 patients. Wiszniewski et al. (2011) stated that the significance of the third mutated allele was unknown, but suggested that mutational load might be important to penetrance of the LCA phenotype. Because LCA manifests very early in life and results in profound vision loss, patients with mutations in other syndromic or nonsyndromic eye disease genes may receive an initial diagnosis of LCA, prior to development of syndromic features or before more thorough phenotyping can be performed (see, e.g., Senior-Loken syndrome-5, 609254).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:35500114
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:35500114
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:35500114
Conflicting/Uncertain
Hetero
Gene:
GSDME
Variant:
c.*30C>T
rsID: rs17274530
Ref Allele: G
Alt Allele: A
Freq: 3.696%uncommon
CADD: 0.169
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:24698996
Likely benign
Hetero
Gene:
SPINK5
Variant:
c.1851T>C
(p.Ala617=)
rsID: rs17718737
Ref Allele: T
Alt Allele: C
Freq: 3.6976%uncommon
CADD: 4.269
ClinVar Submissions (4)
Netherton syndrome is a rare and severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Generalized scaly erythroderma is apparent at or soon after birth and usually persists. Scalp hair is sparse and brittle with a characteristic 'bamboo' shape under light microscopic examination due to invagination of the distal part of the hair shaft to its proximal part. Atopic manifestations include eczema-like rashes, atopic dermatitis, pruritus, hay fever, angioedema, urticaria, high levels of IgE in the serum, and hypereosinophilia. Life-threatening complications are frequent during the neonatal period, including hypernatremic dehydration, hypothermia, extreme weight loss, bronchopneumonia, and sepsis. During childhood, failure to thrive is common as a result of malnutrition, metabolic disorders, chronic erythroderma, persistent cutaneous infections, or enteropathy (summary by Bitoun et al., 2002).
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:148112898
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:148112898
Benign/Likely benign
Hetero
Gene:
KLHL3
Variant:
c.1611G>T
(p.Gly537=)
rsID: rs17171525
Ref Allele: C
Alt Allele: A
Freq: 3.7%uncommon
CADD: 6.566
ClinVar Submissions (2)
Autosomal dominant pseudohypoaldosteronism type I is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by Geller et al., 1998). Autosomal recessive pseudohypoaldosteronism type I (PHA1B; 264350), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:137625877
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:137625877
Benign
Hetero
Gene:
TRPM1
Variant:
c.3686A>C
(p.Asn1229Thr)
rsID: rs17227996
Ref Allele: T
Alt Allele: G
Freq: 3.704%uncommon
CADD: 14.49
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:31002948
Likely benign
Hetero
Gene:
GSDME
Variant:
c.863-6T>C
rsID: rs55735863
Ref Allele: A
Alt Allele: G
Freq: 3.7207%uncommon
CADD: 0.924
ClinVar Submissions (3)
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:24708260
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:24708260
Benign/Likely benign
Hetero
Gene:
SEC23B
Variant:
c.1276G>A
(p.Val426Ile)
rsID: rs41309927
Ref Allele: G
Alt Allele: A
Freq: 3.7287%uncommon
CADD: 18.86
ClinVar Submissions (3)
Congenital dyserythropoietic anemia (CDA) is an inherited blood disorder that affects the development of red blood cells. This disorder is one of many types of anemia, which is a condition characterized by a shortage of red blood cells. This shortage prevents the blood from carrying an adequate supply of oxygen to the body's tissues. The resulting symptoms can include tiredness (fatigue), weakness, pale skin, and other complications.Researchers have identified three major types of CDA: type I, type II, and type III. The types have different genetic causes and different but overlapping patterns of signs and symptoms.CDA type I is characterized by moderate to severe anemia. It is usually diagnosed in childhood or adolescence, although in some cases, the condition can be detected before birth. Many affected individuals have yellowing of the skin and eyes (jaundice) and an enlarged liver and spleen (hepatosplenomegaly). This condition also causes the body to absorb too much iron, which builds up and can damage tissues and organs. In particular, iron overload can lead to an abnormal heart rhythm (arrhythmia), congestive heart failure, diabetes, and chronic liver disease (cirrhosis). Rarely, people with CDA type I are born with skeletal abnormalities, most often involving the fingers and/or toes.The anemia associated with CDA type II can range from mild to severe, and most affected individuals have jaundice, hepatosplenomegaly, and the formation of hard deposits in the gallbladder called gallstones. This form of the disorder is usually diagnosed in adolescence or early adulthood. An abnormal buildup of iron typically occurs after age 20, leading to complications including heart disease, diabetes, and cirrhosis.The signs and symptoms of CDA type III tend to be milder than those of the other types. Most affected individuals do not have hepatosplenomegaly, and iron does not build up in tissues and organs. In adulthood, abnormalities of a specialized tissue at the back of the eye (the retina) can cause vision impairment. Some people with CDA type III also have a blood disorder known as monoclonal gammopathy, which can lead to a cancer of white blood cells (multiple myeloma).Several other variants of CDA have been described, although they appear to be rare and not much is known about them. Once researchers discover the genetic causes of these variants, some of them may be grouped with the three major types of CDA.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 20:18532706
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 20:18532706
Benign/Likely benign
Hetero
Gene:
KDR
Variant:
c.-1G>T
rsID: rs56233104
Ref Allele: C
Alt Allele: A
Freq: 3.7295%uncommon
CADD: 17.04
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 19, 2013
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 4:55125294
Hetero
Gene:
XPC
Variant:
c.1475G>A
(p.Arg492His)
rsID: rs2227999
Ref Allele: C
Alt Allele: T
Freq: 3.7573%uncommon
CADD: 1.074
ClinVar Submissions (2)
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:14158408
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:14158408
Likely benign
Hetero
Gene:
ARSB
Variant:
c.1151G>A
(p.Ser384Asn)
rsID: rs25414
Ref Allele: C
Alt Allele: T
Freq: 3.7661%uncommon
CADD: 13.74
ClinVar Submissions (6)
Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Clinical features and severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism. Intelligence is usually normal (Azevedo et al., 2004).
Last Evaluated: May 31, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:78839418
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 31, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:78839418
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 31, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:78839418
Benign/Likely benign
Hetero
Gene:
LDLR
Variant:
c.*2016G>A
rsID: rs72658879
Ref Allele: G
Alt Allele: A
Freq: 3.7796%uncommon
CADD: 0.973
ClinVar Submissions (1)
Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 19:11133332
Likely benign
Hetero
Gene:
GLI3
Variant:
c.1509C>T
(p.Asn503=)
rsID: rs34020684
Ref Allele: G
Alt Allele: A
Freq: 3.786%uncommon
CADD: 1.282
ClinVar Submissions (3)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:41978737
Benign/Likely benign
Hetero
Gene:
MRE11
Variant:
c.*511G>A
rsID: rs13447749
Ref Allele: C
Alt Allele: T
Freq: 3.8362%uncommon
CADD: 2.356
ClinVar Submissions (1)
Ataxia-telangiectasia-like disorder-1 is an autosomal recessive disorder characterized clinically by progressive cerebellar degeneration resulting in ataxia and oculomotor apraxia. Laboratory studies of patient cells showed increased susceptibility to radiation, consistent with a defect in DNA repair. The disorder shares some phenotypic features of ataxia-telangiectasia (AT; 208900), but telangiectases and immune deficiency are not present in ATLD1 (summary by Hernandez et al., 1993 and Stewart et al., 1999). Genetic Heterogeneity of Ataxia-Telangiectasia-Like Disorder See also ATLD2 (615919), caused by mutation in the PCNA gene (176740) on chromosome 20p12.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:94419614
Likely benign
Homo
Gene:
SYNE2
Variant:
c.14734C>G
(p.Pro4912Ala)
rsID: rs17766354
Ref Allele: C
Alt Allele: G
Freq: 3.8457%uncommon
CADD: 22.3
ClinVar Submissions (5)
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures that begin in early childhood, slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles, and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade.
Last Evaluated: Jun 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:64137874
Last Evaluated: Jun 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:64137874
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:64137874
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:64137874
Benign/Likely benign
Hetero
Gene:
TECTA
Variant:
c.624+11C>G
rsID: rs73599492
Ref Allele: C
Alt Allele: G
Freq: 3.8585%uncommon
CADD: 9.862
ClinVar Submissions (4)
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:121113220
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:121113220
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:121113220
Benign/Likely benign
Hetero
Gene:
SCN4A
Variant:
c.366C>T
(p.Arg122=)
rsID: rs41280108
Ref Allele: G
Alt Allele: A
Freq: 3.8617%uncommon
CADD: 0.056
ClinVar Submissions (6)
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
Congenital myasthenic syndromes (designated as CMS throughout this entry) are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. Cardiac and smooth muscle are usually not involved. Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement. Major findings of the neonatal-onset subtype include: respiratory insufficiency with sudden apnea and cyanosis; feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Arthrogryposis multiplex congenita may also be present. Stridor in infancy may be an important clue to CMS. Later childhood-onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
Hyperkalemic periodic paralysis (hyperPP) is characterized by attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, and trunk), hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness and/or provoking/worsening of an attack by oral potassium intake, normal serum potassium between attacks, and onset before age 20 years. Although the absence of paramyotonia (muscle stiffness aggravated by cold and exercise) was originally postulated as a means of distinguishing hyperPP from paramyotonia congenita (PMC), approximately 45% of individuals with hyperPP have paramyotonia. In approximately half of affected individuals, attacks of flaccid muscle weakness begin in the first decade of life, with 25% reporting their first attack at age ten years or older. Initially infrequent, the attacks then increase in frequency and severity over time until approximately age 50 years, after which the frequency of attacks declines considerably. Potassium-rich food or rest after exercise may precipitate an attack. A cold environment and emotional stress provoke or worsen the attacks. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then disappears. Cardiac arrhythmia or respiratory insufficiency usually does not occur during attacks. Between attacks, approximately half of individuals with hyperPP have mild myotonia (muscle stiffness) that does not impede voluntary movements. More than 80% of individuals with hyperPP older than 40 years report permanent muscle weakness and about one third develop a chronic progressive myopathy.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
Hyperkalemic periodic paralysis (hyperPP) is characterized by attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, and trunk), hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness and/or provoking/worsening of an attack by oral potassium intake, normal serum potassium between attacks, and onset before age 20 years. Although the absence of paramyotonia (muscle stiffness aggravated by cold and exercise) was originally postulated as a means of distinguishing hyperPP from paramyotonia congenita (PMC), approximately 45% of individuals with hyperPP have paramyotonia. In approximately half of affected individuals, attacks of flaccid muscle weakness begin in the first decade of life, with 25% reporting their first attack at age ten years or older. Initially infrequent, the attacks then increase in frequency and severity over time until approximately age 50 years, after which the frequency of attacks declines considerably. Potassium-rich food or rest after exercise may precipitate an attack. A cold environment and emotional stress provoke or worsen the attacks. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then disappears. Cardiac arrhythmia or respiratory insufficiency usually does not occur during attacks. Between attacks, approximately half of individuals with hyperPP have mild myotonia (muscle stiffness) that does not impede voluntary movements. More than 80% of individuals with hyperPP older than 40 years report permanent muscle weakness and about one third develop a chronic progressive myopathy.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands, although it can also affect muscles used for breathing and muscles in the lower body. Unlike many other forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements.Most people—even those without muscle disease—feel that their muscles do not work as well when they are cold. This effect is dramatic in people with paramyotonia congenita. Exposure to cold initially causes muscle stiffness in these individuals, and prolonged cold exposure leads to temporary episodes of mild to severe muscle weakness that may last for several hours at a time. Some older people with paramyotonia congenita develop permanent muscle weakness that can be disabling.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands, although it can also affect muscles used for breathing and muscles in the lower body. Unlike many other forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements.Most people—even those without muscle disease—feel that their muscles do not work as well when they are cold. This effect is dramatic in people with paramyotonia congenita. Exposure to cold initially causes muscle stiffness in these individuals, and prolonged cold exposure leads to temporary episodes of mild to severe muscle weakness that may last for several hours at a time. Some older people with paramyotonia congenita develop permanent muscle weakness that can be disabling.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
In a report on the 37th ENMC Workshop, Rudel and Lehmann-Horn (1997) stated that the sodium channelopathies can be divided into 3 different forms: paramyotonia, potassium-aggravated myotonia, and periodic paralysis. Potassium-aggravated myotonia includes mild myotonia fluctuans, severe myotonia permanens, and acetazolamide-responsive myotonia.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
In a report on the 37th ENMC Workshop, Rudel and Lehmann-Horn (1997) stated that the sodium channelopathies can be divided into 3 different forms: paramyotonia, potassium-aggravated myotonia, and periodic paralysis. Potassium-aggravated myotonia includes mild myotonia fluctuans, severe myotonia permanens, and acetazolamide-responsive myotonia.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63972378
Benign/Likely benign
Hetero
Gene:
AP5Z1
Variant:
c.*2882A>G
rsID: rs113428873
Ref Allele: A
Alt Allele: G
Freq: 3.8696%uncommon
CADD: 2.348
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:4794267
Likely benign
Hetero
Gene:
RBM20
Variant:
c.*552G>C
rsID: rs74156303
Ref Allele: G
Alt Allele: C
Freq: 3.8696%uncommon
CADD: 0.595
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:110836530
Likely benign
Hetero
Gene:
TMIE
Variant:
c.*51C>T
rsID: rs56002857
Ref Allele: C
Alt Allele: T
Freq: 3.8776%uncommon
CADD: 0.401
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:46709739
Likely benign
Hetero
Gene:
INF2
Variant:
c.1227G>T
(p.Ser409=)
rsID: rs3809455
Ref Allele: G
Alt Allele: T
Freq: 3.9501%uncommon
CADD: 2.458
ClinVar Submissions (3)
A clinicopathological syndrome or diagnostic term for a type of glomerular injury that has multiple causes, primary or secondary. Clinical features include PROTEINURIA, reduced GLOMERULAR FILTRATION RATE, and EDEMA. Kidney biopsy initially indicates focal segmental glomerular consolidation (hyalinosis) or scarring which can progress to globally sclerotic glomeruli leading to eventual KIDNEY FAILURE.
Last Evaluated: Sep 06, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:104707494
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 06, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:104707494
Benign
Hetero
Gene:
BFSP2
Variant:
c.1220C>A
(p.Ala407Asp)
rsID: rs79087781
Ref Allele: C
Alt Allele: A
Freq: 3.97%uncommon
CADD: 23
ClinVar Submissions (3)
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule. [HPO:probinson]
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:133472541
Mutations in the BFSP2 gene have been found to cause multiple types of cataract, which have been described as juvenile-onset lamellar, cortical, nuclear embryonic; and congenital nuclear, sutural, stellate, Y-sutural, and punctate cortical.
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:133472541
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:133472541
Benign
Hetero
Gene:
REEP1
Variant:
c.*691G>A
rsID: rs60838463
Ref Allele: C
Alt Allele: T
Freq: 3.9771%uncommon
CADD: 0.164
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:86216409
Benign
Hetero
Gene:
CP
Variant:
c.1950A>C
(p.Gly650=)
rsID: rs1053709
Ref Allele: T
Alt Allele: G
Freq: 4.0114%uncommon
CADD: 11.2
ClinVar Submissions (3)
Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus (DM), and neurologic disease is seen in individuals ranging from age 30 years to older than 70 years. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron deposition in the brain. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or obvious neurologic problems. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition.
Last Evaluated: Jul 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:149186647
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:149186647
Benign/Likely benign
Hetero
Gene:
LAMB1
Variant:
c.4182C>T
(p.Ala1394=)
rsID: rs11545309
Ref Allele: G
Alt Allele: A
Freq: 4.0193%uncommon
CADD: 0.017
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 11, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:107935421
Benign
Hetero
Gene:
GHR
Variant:
c.*1934T>C
rsID: rs62372049
Ref Allele: T
Alt Allele: C
Freq: 4.0408%uncommon
CADD: 9.107
ClinVar Submissions (1)
Laron syndrome is an autosomal recessive disorder characterized by marked short stature that results from failure to generate insulin-like growth factor I (IGF1; 147440) in response to growth hormone (GH; 139250). GH levels are normal or increased. The disorder is caused by dysfunction of the growth hormone receptor. A Laron syndrome-like phenotype associated with immunodeficiency (245590) is caused by a postreceptor defect, i.e., mutation in the STAT5B gene (604260). Patients with mutations in the GHR gene that cause only partial insensitivity to growth hormone have a form of short stature (604271).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:42721358
Likely benign
Hetero
Gene:
OGDH
Variant:
c.3063C>T
(p.Asn1021=)
rsID: rs61756584
Ref Allele: C
Alt Allele: T
Freq: 4.0512%uncommon
CADD: 0.441
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 22, 2016
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:44707990
Benign
Hetero
Gene:
OGDH
Variant:
c.2988C>T
(p.Thr996=)
rsID: rs61756583
Ref Allele: C
Alt Allele: T
Freq: 4.0528%uncommon
CADD: 0.695
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 22, 2016
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:44707915
Benign
Hetero
Gene:
OSTM1
Variant:
c.*2053C>T
rsID: rs17069215
Ref Allele: G
Alt Allele: A
Freq: 4.1061%uncommon
CADD: 5.023
ClinVar Submissions (1)
A rare genetic disorder inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern. In the majority of cases it is caused by mutations in the CLCN7, TCIRG1, or IKBKG genes. It is characterized by excessive bone formation due to the failure of osteoclasts to resorb bone. It manifests with deformities, fractures, hepatosplenomegaly, anemia, and extramedullary hematopoiesis.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:108042732
Likely benign
Hetero
Gene:
OSTM1
Variant:
c.*1352A>G
rsID: rs9372179
Ref Allele: T
Alt Allele: C
Freq: 4.1061%uncommon
CADD: 2.742
ClinVar Submissions (1)
A rare genetic disorder inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern. In the majority of cases it is caused by mutations in the CLCN7, TCIRG1, or IKBKG genes. It is characterized by excessive bone formation due to the failure of osteoclasts to resorb bone. It manifests with deformities, fractures, hepatosplenomegaly, anemia, and extramedullary hematopoiesis.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:108043433
Likely benign
Hetero
Gene:
OSTM1
Variant:
c.*1334T>C
rsID: rs9374008
Ref Allele: A
Alt Allele: G
Freq: 4.1061%uncommon
CADD: 3.083
ClinVar Submissions (1)
A rare genetic disorder inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern. In the majority of cases it is caused by mutations in the CLCN7, TCIRG1, or IKBKG genes. It is characterized by excessive bone formation due to the failure of osteoclasts to resorb bone. It manifests with deformities, fractures, hepatosplenomegaly, anemia, and extramedullary hematopoiesis.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:108043451
Likely benign
Hetero
Gene:
JMJD1C
Variant:
c.1547C>G
(p.Thr516Ser)
rsID: rs41274074
Ref Allele: G
Alt Allele: C
Freq: 4.1069%uncommon
CADD: 13.92
ClinVar Submissions (1)
Early infantile epileptic encephalopathy is characterized by onset during the first months of life of erratic refractory seizures, usually myoclonic. The prognosis is poor, and most children with the condition either die within 1 to 2 years after birth or survive in a persistent vegetative state. The EEG pattern often shows a suppression-burst pattern with high-voltage bursts of slow waves mixed with multifocal spikes alternating with isoelectric suppression phases (Molinari et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Last Evaluated: Aug 22, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:63214620
Benign
Hetero
Gene:
DBT
Variant:
c.1210-10T>A
rsID: rs183058253
Ref Allele: A
Alt Allele: T
Freq: 4.1133%uncommon
CADD: 8.189
ClinVar Submissions (4)
Maple syrup urine disease (MSUD) is classified as classic or intermediate. Twelve hours after birth, untreated neonates with classic MSUD have a maple syrup odor in cerumen; by 12-24 hours, elevated plasma concentrations of branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) and allo-isoleucine, as well as a generalized disturbance of plasma amino acid concentration ratios; by age two to three days, ketonuria, irritability, and poor feeding; by age four to five days, deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling." By age seven to ten days, coma and central respiratory failure may supervene. Individuals with intermediate MSUD have partial BCKAD enzyme deficiency that only manifests intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy during sufficient catabolic stress.
Last Evaluated: Sep 06, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:100206311
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 06, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:100206311
Benign/Likely benign
Hetero
Gene:
DSE
Variant:
c.1142T>C
(p.Val381Ala)
rsID: rs41313440
Ref Allele: T
Alt Allele: C
Freq: 4.1213%uncommon
CADD: 13.79
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 06, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:116435610
Benign
Hetero
Gene:
WRN
Variant:
c.355+20A>T
rsID: rs4987239
Ref Allele: A
Alt Allele: T
Freq: 4.1253%uncommon
CADD: 0.47
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:31064454
Benign
Hetero
Gene:
RAX
Variant:
c.*376C>T
rsID: rs3744893
Ref Allele: G
Alt Allele: A
Freq: 4.1452%uncommon
CADD: 2.607
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:59268628
Likely benign
Hetero
Gene:
GPR179
Variant:
c.2650C>T
(p.Arg884Trp)
rsID: rs72832277
Ref Allele: G
Alt Allele: A
Freq: 4.1571%uncommon
CADD: 16.09
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:38330919
Likely benign
Hetero
Gene:
NEK2
Variant:
c.765+14G>T
rsID: rs2289725
Ref Allele: C
Alt Allele: A
Freq: 4.1858%uncommon
CADD: 0.084
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:211670267
Benign
Hetero
Gene:
PDGFRA
Variant:
c.368-3C>T
rsID: rs55947416
Ref Allele: C
Alt Allele: T
Freq: 4.1874%uncommon
CADD: 16.12
ClinVar Submissions (2)
Gastrointestinal stromal tumors are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (Miettinen et al., 1999, 1999). GISTs can also be seen in neurofibromatosis-1 (NF1; 162200) due to mutations in the NF1 gene, and are thus distinct from the GISTs described here. Sandberg and Bridge (2002) reviewed the cytogenetics and molecular genetics of gastrointestinal stromal tumors. Coffey et al. (2007) reviewed the clinical features, pathogenesis, and molecular treatments of Menetrier disease (137280) and GIST, both of which are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:54263664
PDGFRA-associated chronic eosinophilic leukemia is a form of blood cell cancer characterized by an elevated number of cells called eosinophils in the blood. These cells help fight infections by certain parasites and are involved in the inflammation associated with allergic reactions. However, these circumstances do not account for the increased number of eosinophils in PDGFRA-associated chronic eosinophilic leukemia.Another characteristic feature of PDGFRA-associated chronic eosinophilic leukemia is organ damage caused by the excess eosinophils. Eosinophils release substances to aid in the immune response, but the release of excessive amounts of these substances causes damage to one or more organs, most commonly the heart, skin, lungs, or nervous system. Eosinophil-associated organ damage can lead to a heart condition known as eosinophilic endomyocardial disease, skin rashes, coughing, difficulty breathing, swelling (edema) in the lower limbs, confusion, changes in behavior, or impaired movement or sensations. People with PDGFRA-associated chronic eosinophilic leukemia can also have an enlarged spleen (splenomegaly) and elevated levels of certain chemicals called vitamin B12 and tryptase in the blood.Some people with PDGFRA-associated chronic eosinophilic leukemia have an increased number of other types of white blood cells, such as neutrophils or mast cells. Occasionally, people with PDGFRA-associated chronic eosinophilic leukemia develop other blood cell cancers, such as acute myeloid leukemia or B-cell or T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma.PDGFRA-associated chronic eosinophilic leukemia is often grouped with a related condition called hypereosinophilic syndrome. These two conditions have very similar signs and symptoms; however, the cause of hypereosinophilic syndrome is unknown.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:54263664
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:54263664
Benign/Likely benign
Hetero
Gene:
OGDH
Variant:
c.3052G>A
(p.Val1018Ile)
rsID: rs2070607
Ref Allele: G
Alt Allele: A
Freq: 4.2105%uncommon
CADD: 15.91
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 22, 2016
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:44707979
Benign
Hetero
Gene:
CACNA1C
Variant:
c.5292C>T
(p.Asn1764=)
rsID: rs72552065
Ref Allele: C
Alt Allele: T
Freq: 4.2176%uncommon
CADD: 0.586
ClinVar Submissions (6)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Aug 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2679644
Last Evaluated: Aug 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2679644
Last Evaluated: Aug 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2679644
A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.
Last Evaluated: Aug 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2679644
Timothy syndrome is a multisystem disorder characterized by cardiac, hand/foot, facial, and neurodevelopmental features. Typical cardiac findings include a rate-corrected QT interval >480 ms, functional 2:1 AV block with bradycardia, tachyarrhythmias, and congenital heart defects (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy). The diagnosis of Timothy syndrome is generally made within the first few days of life although it may be suspected prenatally due to 2:1 AV block or bradycardia in the fetus. Hand/foot findings are unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three. Facial findings include depressed nasal bridge, low-set ears, thin vermilion border of the upper lip, and round face. Neuropsychiatric involvement includes global developmental delays and autism spectrum disorders. Ventricular tachyarrhythmia is the leading cause of death, followed by infection and complications of intractable hypoglycemia. Average age of death is 2.5 years.
Last Evaluated: Aug 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2679644
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2679644
Benign/Likely benign
Hetero
Gene:
P3H1
Variant:
c.139G>T
(p.Ala47Ser)
rsID: rs55716016
Ref Allele: C
Alt Allele: A
Freq: 4.2352%uncommon
CADD: 16.17
ClinVar Submissions (3)
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Cabral et al. (2007) described a form of autosomal recessive OI, which they designated OI type VIII, characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses.
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:42766833
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:42766833
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:42766833
Benign
Hetero
Gene:
HGF
Variant:
c.910G>A
(p.Glu304Lys)
rsID: rs5745687
Ref Allele: C
Alt Allele: T
Freq: 4.2583%uncommon
CADD: 16.75
ClinVar Submissions (5)
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:81729735
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:81729735
Benign/Likely benign
Hetero
Gene:
FLT4
Variant:
c.677-28G>A
rsID: rs56361806
Ref Allele: C
Alt Allele: T
Freq: 4.263%uncommon
CADD: 0.023
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:180629863
Benign
Hetero
Gene:
ARL6
Variant:
c.186-18T>C
rsID: rs77906443
Ref Allele: T
Alt Allele: C
Freq: 4.2686%uncommon
CADD: 0.673
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:97780597
Benign
Hetero
Gene:
SCN5A
Variant:
c.2788-6C>T
rsID: rs41260344
Ref Allele: G
Alt Allele: A
Freq: 4.2742%uncommon
CADD: 0.265
ClinVar Submissions (5)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:38581377
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:38581377
A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:38581377
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:38581377
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:38581377
Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the ECG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7), hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8), and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:38581377
A condition caused by dysfunctions related to the SINOATRIAL NODE including impulse generation (CARDIAC SINUS ARREST) and impulse conduction (SINOATRIAL EXIT BLOCK). It is characterized by persistent BRADYCARDIA, chronic ATRIAL FIBRILLATION, and failure to resume sinus rhythm following CARDIOVERSION. This syndrome can be congenital or acquired, particularly after surgical correction for heart defects.
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:38581377
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:38581377
Benign/Likely benign
Hetero
Gene:
COL10A1
Variant:
c.1809G>C
(p.Val603=)
rsID: rs2228548
Ref Allele: C
Alt Allele: G
Freq: 4.3044%uncommon
CADD: 11.91
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:116120307
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:116120307
Benign
Hetero
Gene:
SMARCA4
Variant:
c.4053C>T
(p.Asp1351=)
rsID: rs28997582
Ref Allele: C
Alt Allele: T
Freq: 4.3196%uncommon
CADD: 0.414
ClinVar Submissions (5)
Coffin-Siris syndrome is a multiple malformation syndrome characterized by mental retardation associated with coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. Other more variable features may include poor overall growth, craniofacial abnormalities, spinal anomalies, and congenital heart defects (review by Vergano and Deardorff, 2014). Mutations in the ARID1B gene are the most common cause of Coffin-Siris syndrome (Wieczorek et al., 2013). Genetic Heterogeneity of Coffin-Siris Syndrome Forms of Coffin-Siris syndrome have been shown to be caused by mutations in genes encoding subunits of the SWI/SNF complex, also known as the BAF complex, which functions as a chromatin remodeling factor. These include CSS2 (614607), caused by mutation in the ARID1A gene (603024); CSS3 (614608), caused by mutation in the SMARCB1 gene (601607); CSS4 (614609), caused by mutation in the SMARCA4 gene (603254); CSS5 (616938), caused by mutation in the SMARCE1 gene (603111); CSS6 (617808), caused by mutation in the ARID2 gene (609539); and CSS7 (618027), caused by mutation in the DPF2 gene (601671). A similar phenotype, Nicolaides-Baraitser syndrome (NCBRS; 601358), is also caused by mutation in a subunit of this complex, i.e., SMARCA2 (600014).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:11035015
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:11035015
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:11035015
Benign
Hetero
Gene:
ARHGEF28
Variant:
c.823A>C
(p.Arg275=)
rsID: rs10473959
Ref Allele: A
Alt Allele: C
Freq: 4.3435%uncommon
CADD: 15.7
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:73776679
Benign
Hetero
Gene:
BRCA2
Variant:
c.9256+4605G>A
rsID: rs10492396
Ref Allele: G
Alt Allele: A
Freq: 4.3451%uncommon
CADD: 14.65
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Jan 12, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32384750
Expert Reviewed Benign
Hetero
Gene:
PRX
Variant:
c.3394G>A
(p.Gly1132Arg)
rsID: rs268674
Ref Allele: C
Alt Allele: T
Freq: 4.3594%uncommon
CADD: 6.946
ClinVar Submissions (4)
Charcot-Marie-Tooth disease type 4 (CMT4) belongs to the genetically heterogeneous group of CMT peripheral sensorimotor polyneuropathy diseases. Type 4 is less common and often limited to certain ethnic groups. Patients present with the typical CMT phenotype along with typical features of progressive, distally accentuated weakness and atrophy of muscles innervated by the peroneal nerve in the lower limbs, followed by weakness and atrophy of hands, sensory loss, and characteristic foot abnormalities.
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:40394958
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:40394958
Benign
Hetero
Gene:
XIAP
Variant:
c.*6422T>A
rsID: rs5911725
Ref Allele: T
Alt Allele: A
Freq: 4.3682%uncommon
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:123913603
Benign
Hetero
Gene:
BRCA2
Variant:
c.425+147G>T
rsID: rs4942423
Ref Allele: G
Alt Allele: T
Freq: 4.3936%uncommon
CADD: 3.011
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Jan 12, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32325331
Expert Reviewed Benign
Hetero
Gene:
ADAMTS13
Variant:
c.173-18C>T
rsID: rs35410697
Ref Allele: C
Alt Allele: T
Freq: 4.4024%uncommon
CADD: 1.195
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:133424303
Benign
Hetero
Gene:
TSHZ1
Variant:
c.1029G>A
(p.Pro343=)
rsID: rs34095753
Ref Allele: G
Alt Allele: A
Freq: 4.4032%uncommon
CADD: 0.082
ClinVar Submissions (1)
Altmann (1955) was the first to describe a congenital aural atresia (CAA) classification, which has been modified over the years (Cremers et al., 1988; Schuknecht, 1989; Jahrsdoerfer et al., 1992). In CAA type I, there is bony or fibrous atresia of the lateral part of the external auditory canal and an almost normal medial part and middle ear. CAA type II is the most frequent type and is characterized by partial or total aplasia of the external auditory canal. CAA type IIA involves an external auditory canal with either complete bony atresia of the medial part or partial aplasia that ends blindly in a fistula leading to a rudimentary tympanic membrane. CAA type IIB is characterized by bony stenosis of the total length of the external auditory canal. CAA type III involves bony atresia of the external auditory canal and a very small or absent middle-ear cavity (summary by Feenstra et al., 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:75286571
Benign
Hetero
Gene:
DUOX2
Variant:
c.2944C>G
(p.Pro982Ala)
rsID: rs61730030
Ref Allele: G
Alt Allele: C
Freq: 4.4167%uncommon
CADD: 0.96
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:45100816
Benign
Hetero
Gene:
HCN4
Variant:
c.107G>A
(p.Gly36Glu)
rsID: rs143090627
Ref Allele: C
Alt Allele: T
Freq: 4.439%uncommon
CADD: 19.04
ClinVar Submissions (5)
Last Evaluated: Apr 07, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:73368164
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 07, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:73368164
Benign
Hetero
Gene:
SLC11A1
Variant:
c.1627G>A
(p.Asp543Asn)
rsID: rs17235409
Ref Allele: G
Alt Allele: A
Freq: 4.4422%uncommon
CADD: 3.016
ClinVar Submissions (1)
Buruli ulcer is an infectious disease prevalent in many tropical and subtropical regions caused by infection with Mycobacterium ulcerans. It is the third most frequent mycobacterial disease in humans worldwide, after tuberculosis (607948) and leprosy (246300). Lesions are most common on exposed parts of the body, especially the limbs. Buruli ulcer derives its name from a county in Uganda, East Africa, north of Kampala, where the disease was found in the late 1950s in hundreds of people living near marshes and riverine areas near the Nile River (Clancey et al., 1961; Barker, 1971). The disease was first described in the medical literature in 1948 in a report on patients in Australia (MacCallum et al., 1948). Patients have also been reported from tropical areas in Latin America and Asia (Stienstra et al., 2006; van der Werf et al., 2005).
Last Evaluated: Apr 01, 2006
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: risk factor
Assembly: GRCh38
Chromosome/Position: 2:218395009
OMIM Allelic Variant: 600266.0002
Hetero
Gene:
PIK3R2
Variant:
c.2127C>T
(p.Thr709=)
rsID: rs112813367
Ref Allele: C
Alt Allele: T
Freq: 4.4597%uncommon
CADD: 1.014
ClinVar Submissions (2)
The MPPH syndrome is a developmental brain disorder characterized by megalencephaly (brain overgrowth) with the cortical malformation bilateral perisylvian polymicrogyria (BPP). At birth the occipital frontal circumference (OFC) ranges from normal to 6 standard deviations (SD) above the mean for age, sex, and gestational age; in older individuals the range is from 3 to 10 SD above the mean. A variable degree of ventriculomegaly is seen in almost all children with MPPH syndrome; nearly 50% of those have frank hydrocephalus. Neurologic problems associated with BPP include oromotor dysfunction (100%), epilepsy (50%), and mild to severe intellectual disability (100%). Postaxial hexadactyly occurs in 50% of individuals with MPPH syndrome.
Last Evaluated: Jun 28, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:18169234
Benign
Hetero
Gene:
TAT
Variant:
c.-113G>T
rsID: rs117706276
Ref Allele: C
Alt Allele: A
Freq: 4.4677%uncommon
CADD: 2.673
ClinVar Submissions (1)
An increased concentration of tyrosine in the blood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:71577109
Likely benign
Hetero
Gene:
TGFBI
Variant:
c.460-16C>T
rsID: rs41298960
Ref Allele: C
Alt Allele: T
Freq: 4.5019%uncommon
CADD: 5.723
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:136046835
Benign
Hetero
Gene:
TSEN54
Variant:
c.1447C>G
(p.Pro483Ala)
rsID: rs62088470
Ref Allele: C
Alt Allele: G
Freq: 4.5075%uncommon
CADD: 26.4
ClinVar Submissions (4)
Pontocerebellar hypoplasia is a group of related conditions that affect the development of the brain. The term "pontocerebellar" refers to the pons and the cerebellum, which are the brain structures that are most severely affected in many forms of this disorder. The pons is located at the base of the brain in an area called the brainstem, where it transmits signals between the cerebellum and the rest of the brain. The cerebellum, which is located at the back of the brain, normally coordinates movement. The term "hypoplasia" refers to the underdevelopment of these brain regions.Pontocerebellar hypoplasia also causes impaired growth of other parts of the brain, leading to an unusually small head size (microcephaly). This microcephaly is usually not apparent at birth but becomes noticeable as brain growth continues to be slow in infancy and early childhood.Researchers have described at least ten types of pontocerebellar hypoplasia. All forms of this condition are characterized by impaired brain development, delayed development overall, problems with movement, and intellectual disability. The brain abnormalities are usually present at birth, and in some cases they can be detected before birth. Many children with pontocerebellar hypoplasia live only into infancy or childhood, although some affected individuals have lived into adulthood.The two major forms of pontocerebellar hypoplasia are designated as type 1 (PCH1) and type 2 (PCH2). In addition to the brain abnormalities described above, PCH1 causes problems with muscle movement resulting from a loss of specialized nerve cells called motor neurons in the spinal cord, similar to another genetic disorder known as spinal muscular atrophy. Individuals with PCH1 also have very weak muscle tone (hypotonia), joint deformities called contractures, vision impairment, and breathing and feeding problems that are evident from early infancy.Common features of PCH2 include a lack of voluntary motor skills (such as grasping objects, sitting, or walking), problems with swallowing (dysphagia), and an absence of communication, including speech. Affected children typically develop temporary jitteriness (generalized clonus) in early infancy, abnormal patterns of movement described as chorea or dystonia, and stiffness (spasticity). Many also have impaired vision and seizures.The other forms of pontocerebellar hypoplasia, designated as type 3 (PCH3) through type 10 (PCH10), appear to be rare and have each been reported in only a small number of individuals. Because the different types have overlapping features, and some are caused by mutations in the same genes, researchers have proposed that the types be considered as a spectrum instead of distinct conditions.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75524278
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75524278
Benign/Likely benign
Hetero
Gene:
SLC33A1
Variant:
c.*1141A>T
rsID: rs77664705
Ref Allele: T
Alt Allele: A
Freq: 4.5083%uncommon
CADD: 0.08
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:155827069
Likely benign
Hetero
Gene:
ACOX1
Variant:
c.*633G>C
rsID: rs71382188
Ref Allele: C
Alt Allele: G
Freq: 4.5227%uncommon
CADD: 0.577
ClinVar Submissions (1)
Peroxisomal acyl-CoA oxidase deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also D-bifunctional protein deficiency (261515), caused by mutation in the HSD17B4 gene (601860) on chromosome 5q2. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (see 601539) (Watkins et al., 1995).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75946115
Likely benign
Hetero
Gene:
INSR
Variant:
c.2997C>T
(p.Tyr999=)
rsID: rs1799815
Ref Allele: G
Alt Allele: A
Freq: 4.5235%uncommon
CADD: 1.735
ClinVar Submissions (2)
Type A insulin resistance syndrome is a rare disorder characterized by severe insulin resistance, a condition in which the body's tissues and organs do not respond properly to the hormone insulin. Insulin normally helps regulate blood sugar levels by controlling how much sugar (in the form of glucose) is passed from the bloodstream into cells to be used as energy. In people with type A insulin resistance syndrome, insulin resistance impairs blood sugar regulation and ultimately leads to a condition called diabetes mellitus, in which blood sugar levels can become dangerously high.Severe insulin resistance also underlies the other signs and symptoms of type A insulin resistance syndrome. In affected females, the major features of the condition become apparent in adolescence. Many affected females do not begin menstruation by age 16 (primary amenorrhea) or their periods may be light and irregular (oligomenorrhea). They develop cysts on the ovaries and excessive body hair growth (hirsutism). Most affected females also develop a skin condition called acanthosis nigricans, in which the skin in body folds and creases becomes thick, dark, and velvety. Unlike most people with insulin resistance, females with type A insulin resistance syndrome are usually not overweight.The features of type A insulin resistance syndrome are more subtle in affected males. Some males have low blood sugar (hypoglycemia) as the only sign; others may also have acanthosis nigricans. In many cases, males with this condition come to medical attention only when they develop diabetes mellitus in adulthood.Type A insulin resistance syndrome is one of a group of related conditions described as inherited severe insulin resistance syndromes. These disorders, which also include Donohue syndrome and Rabson-Mendenhall syndrome, are considered part of a spectrum. Type A insulin resistance syndrome represents the mildest end of the spectrum: its features often do not become apparent until puberty or later, and it is generally not life-threatening.
Last Evaluated: Jan 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7125508
INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS). DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.
Last Evaluated: Jan 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7125508
INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS). DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.
Last Evaluated: Jan 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7125508
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7125508
Benign
Hetero
Gene:
GAA
Variant:
c.1888+21G>A
rsID: rs2304837
Ref Allele: G
Alt Allele: A
Freq: 4.5378%uncommon
CADD: 4.656
ClinVar Submissions (3)
Pompe disease is classified by age of onset, organ involvement, severity, and rate of progression. Infantile-onset Pompe disease (IOPD; individuals with onset before age 12 months with cardiomyopathy) may be apparent in utero but more typically onset is at the median age of four months with hypotonia, generalized muscle weakness, feeding difficulties, failure to thrive, respiratory distress, and hypertrophic cardiomyopathy. Without treatment by enzyme replacement therapy (ERT), IOPD commonly results in death by age two years from progressive left ventricular outflow obstruction and respiratory insufficiency. Late-onset Pompe disease (LOPD; including: (a) individuals with onset before age 12 months without cardiomyopathy; and (b) all individuals with onset after age 12 months) is characterized by proximal muscle weakness and respiratory insufficiency; clinically significant cardiac involvement is uncommon.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:80112732
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:80112732
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:80112732
Benign
Hetero
Gene:
GAA
Variant:
c.2065G>A
(p.Glu689Lys)
rsID: rs1800309
Ref Allele: G
Alt Allele: A
Freq: 4.5426%uncommon
CADD: 18.3
ClinVar Submissions (8)
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Low clinical importance, Uncertain benign — This is also known as the GAA*4 allozyme is frequent in the Asian population and appears to have somewhat reduced enzyme activity. Kroos et al. rule out pathogenic effect.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
FOXF1
Variant:
c.*591G>T
rsID: rs75593355
Ref Allele: G
Alt Allele: T
Freq: 4.5585%uncommon
CADD: 0.233
ClinVar Submissions (1)
Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity (Boggs et al., 1994). Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period (Vassal et al., 1998). Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs (Sen et al., 2004).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:86513676
Likely benign
Hetero
Gene:
EFHC1
Variant:
c.545G>A
(p.Arg182His)
rsID: rs3804505
Ref Allele: G
Alt Allele: A
Freq: 4.5688%uncommon
CADD: 14.54
ClinVar Submissions (4)
Last Evaluated: Aug 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:52438563
OMIM Allelic Variant: 608815.0001
Last Evaluated: Aug 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:52438563
OMIM Allelic Variant: 608815.0001
Last Evaluated: Aug 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:52438563
OMIM Allelic Variant: 608815.0001
Low clinical importance, Likely benign — Probably benign. OMIM appears to incorrectly interpret literature as linking this variant to juvenile myoclonic epilepsy; the authors report it as a polymorphism.
Benign
Hetero
Gene:
DUOX2
Variant:
c.2102G>A
(p.Arg701Gln)
rsID: rs113400262
Ref Allele: C
Alt Allele: T
Freq: 4.5744%uncommon
CADD: 13.46
ClinVar Submissions (2)
Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.Signs and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.Congenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:45106171
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:45106171
Benign/Likely benign
Hetero
Gene:
PDE6B
Variant:
c.1467+20C>T
rsID: rs74464382
Ref Allele: C
Alt Allele: T
Freq: 4.5848%uncommon
CADD: 6.073
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 18, 2011
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:659037
Benign
Hetero
Gene:
PNKD
Variant:
c.*1193C>T
rsID: rs76752438
Ref Allele: C
Alt Allele: T
Freq: 4.5975%uncommon
CADD: 2.98
ClinVar Submissions (1)
Familial paroxysmal nonkinesigenic dyskinesia (referred to as familial PNKD in this entry) is characterized by unilateral or bilateral involuntary movements; attacks are spontaneous or precipitated by alcohol, coffee or tea, chocolate, excitement, stress, or fatigue. Attacks involve dystonic posturing with choreic and ballistic movements, may be accompanied by a preceding aura, occur while the individual is awake, and are not associated with seizures. Attacks last minutes to hours and rarely occur more than once per day. Attack frequency, duration, severity, and combinations of symptoms vary within and among families. Age of onset is typically in childhood or early teens, but can be as late as age 50 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:218346174
Benign
Hetero
Gene:
CRTAP
Variant:
c.*1919A>G
rsID: rs4429578
Ref Allele: A
Alt Allele: G
Freq: 4.5983%uncommon
CADD: 6.114
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:33144367
Likely benign
Hetero
Gene:
FOXF1
Variant:
c.*1147T>C
rsID: rs77088019
Ref Allele: T
Alt Allele: C
Freq: 4.6023%uncommon
CADD: 17.63
ClinVar Submissions (1)
Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity (Boggs et al., 1994). Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period (Vassal et al., 1998). Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs (Sen et al., 2004).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:86514232
Likely benign
Hetero
Gene:
AP5Z1
Variant:
c.*250T>G
rsID: rs12154621
Ref Allele: T
Alt Allele: G
Freq: 4.6111%uncommon
CADD: 0.546
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:4791635
Likely benign
Hetero
Gene:
TCF12
Variant:
c.297A>G
(p.Pro99=)
rsID: rs34560099
Ref Allele: A
Alt Allele: G
Freq: 4.6158%uncommon
CADD: 18.72
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 12, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:57091863
Benign
Hetero
Gene:
GNPTAB
Variant:
c.*1457A>G
rsID: rs10219650
Ref Allele: T
Alt Allele: C
Freq: 4.6174%uncommon
CADD: 7.831
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101745707
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101745707
Likely benign
Hetero
Gene:
SLC2A1
Variant:
c.1065A>G
(p.Leu355=)
rsID: rs2228490
Ref Allele: T
Alt Allele: C
Freq: 4.6373%uncommon
CADD: 2.56
ClinVar Submissions (6)
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:42928941
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:42928941
GLUT1 deficiency syndrome is a disorder affecting the nervous system that can have a variety of neurological signs and symptoms. Approximately 90 percent of affected individuals have a form of the disorder often referred to as common GLUT1 deficiency syndrome. These individuals generally have frequent seizures (epilepsy) beginning in the first months of life. In newborns, the first sign of the disorder may be involuntary eye movements that are rapid and irregular. Babies with common GLUT1 deficiency syndrome have a normal head size at birth, but growth of the brain and skull is often slow, which can result in an abnormally small head size (microcephaly). People with this form of GLUT1 deficiency syndrome may have developmental delay or intellectual disability. Most affected individuals also have other neurological problems, such as stiffness caused by abnormal tensing of the muscles (spasticity), difficulty in coordinating movements (ataxia), and speech difficulties (dysarthria). Some experience episodes of confusion, lack of energy (lethargy), headaches, or muscle twitches (myoclonus), particularly during periods without food (fasting).About 10 percent of individuals with GLUT1 deficiency syndrome have a form of the disorder often known as non-epileptic GLUT1 deficiency syndrome, which is usually less severe than the common form. People with the non-epileptic form do not have seizures, but they may still have developmental delay and intellectual disability. Most have movement problems such as ataxia or involuntary tensing of various muscles (dystonia); the movement problems may be more pronounced than in the common form.Several conditions that were originally given other names have since been recognized to be variants of GLUT1 deficiency syndrome. These include paroxysmal choreoathetosis with spasticity (dystonia 9); paroxysmal exercise-induced dyskinesia and epilepsy (dystonia 18); and certain types of epilepsy. In rare cases, people with variants of GLUT1 deficiency syndrome produce abnormal red blood cells and have uncommon forms of a blood condition known as anemia, which is characterized by a shortage of red blood cells.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:42928941
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:42928941
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:42928941
Benign
Hetero
Gene:
SYNE2
Variant:
c.16722A>G
(p.Gln5574=)
rsID: rs17101704
Ref Allele: A
Alt Allele: G
Freq: 4.6676%uncommon
CADD: 17.06
ClinVar Submissions (3)
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures that begin in early childhood, slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles, and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:64167349
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:64167349
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:64167349
Benign
Hetero
Gene:
TCIRG1
Variant:
c.384C>T
(p.His128=)
rsID: rs3808973
Ref Allele: C
Alt Allele: T
Freq: 4.6756%uncommon
CADD: 5.745
ClinVar Submissions (2)
A rare genetic disorder inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern. In the majority of cases it is caused by mutations in the CLCN7, TCIRG1, or IKBKG genes. It is characterized by excessive bone formation due to the failure of osteoclasts to resorb bone. It manifests with deformities, fractures, hepatosplenomegaly, anemia, and extramedullary hematopoiesis.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:68042830
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:68042830
Benign/Likely benign
Hetero
Gene:
GALNS
Variant:
c.692C>G
(p.Ala231Gly)
rsID: rs34745339
Ref Allele: G
Alt Allele: C
Freq: 4.7066%uncommon
CADD: 23.9
ClinVar Submissions (6)
Mucopolysaccharidosis type IV (MPS IV), also known as Morquio syndrome, is a progressive condition that mainly affects the skeleton. The rate at which symptoms worsen varies among affected individuals.The first signs and symptoms of MPS IV usually become apparent during early childhood. Affected individuals develop various skeletal abnormalities, including short stature, knock knees, and abnormalities of the ribs, chest, spine, hips, and wrists. People with MPS IV often have joints that are loose and very flexible (hypermobile), but they may also have restricted movement in certain joints. A characteristic feature of this condition is underdevelopment (hypoplasia) of a peg-like bone in the neck called the odontoid process. The odontoid process helps stabilize the spinal bones in the neck (cervical vertebrae). Odontoid hypoplasia can lead to misalignment of the cervical vertebrae, which may compress and damage the spinal cord, resulting in paralysis or death.In people with MPS IV, the clear covering of the eye (cornea) typically becomes cloudy, which can cause vision loss. Some affected individuals have recurrent ear infections and hearing loss. The airway may become narrow in some people with MPS IV, leading to frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea). Other common features of this condition include mildly "coarse" facial features, thin tooth enamel, multiple cavities, heart valve abnormalities, a mildly enlarged liver (hepatomegaly), and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). Unlike some other types of mucopolysaccharidosis, MPS IV does not affect intelligence.The life expectancy of individuals with MPS IV depends on the severity of symptoms. Severely affected individuals may survive only until late childhood or adolescence. Those with milder forms of the disorder usually live into adulthood, although their life expectancy may be reduced. Spinal cord compression and airway obstruction are major causes of death in people with MPS IV.
Last Evaluated: Jun 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:88835791
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:88835791
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:88835791
Benign/Likely benign
Hetero
Gene:
RYR1
Variant:
c.6178G>T
(p.Gly2060Cys)
rsID: rs35364374
Ref Allele: G
Alt Allele: T
Freq: 4.7098%uncommon
CADD: 22.2
ClinVar Submissions (9)
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.
Last Evaluated: Mar 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:38492540
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.
Last Evaluated: Mar 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:38492540
Last Evaluated: Mar 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:38492540
Central core disease (CCD) is characterized by muscle weakness ranging from mild to severe. Most affected individuals have mild disease with symmetric proximal muscle weakness and variable involvement of facial and neck muscles. The extraocular muscles are often spared. Motor development is usually delayed, but in general, most affected individuals acquire independent ambulation. Life span is usually normal. Severe disease is early in onset with profound hypotonia often accompanied by poor fetal movement, spinal deformities, hip dislocation, joint contractures, poor suck, and respiratory insufficiency requiring assisted ventilation. The outcome ranges from death in infancy to survival beyond age five years. The weakness in CCD is not typically progressive.
Last Evaluated: Mar 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:38492540
Last Evaluated: Mar 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:38492540
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:38492540
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:38492540
Benign
Hetero
Gene:
MMAB
Variant:
c.*368T>A
rsID: rs773284148
Ref Allele: A
Alt Allele: T
Freq: 4.7217%uncommon
CADD: 0.103
ClinVar Submissions (1)
Isolated methylmalonic acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109556660
Likely benign
Hetero
Gene:
ADGRV1
Variant:
c.8291C>T
(p.Ser2764Leu)
rsID: rs16869016
Ref Allele: C
Alt Allele: T
Freq: 4.7433%uncommon
CADD: 6.304
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 29, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:90704393
Benign
Hetero
Gene:
ATP6AP2
Variant:
c.268C>G
(p.Pro90Ala)
rsID: rs9014
Ref Allele: C
Alt Allele: G
Freq: 4.7759%uncommon
ClinVar Submissions (4)
Last Evaluated: Aug 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:40591333
Last Evaluated: Aug 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:40591333
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:40591333
Benign
Hetero
Gene:
PDE6B
Variant:
c.915G>A
(p.Thr305=)
rsID: rs75695239
Ref Allele: G
Alt Allele: A
Freq: 4.7783%uncommon
CADD: 0.054
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:654142
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:654142
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:654142
Benign
Hetero
Gene:
MAP3K1
Variant:
c.1566C>T
(p.Thr522=)
rsID: rs2229882
Ref Allele: C
Alt Allele: T
Freq: 4.7855%uncommon
CADD: 0.148
ClinVar Submissions (1)
Nonsyndromic disorders of testicular development are a group of conditions characterized by the following: A generally normal physical examination with absence of clinical findings involving organ systems other than the reproductive organs. A normal 46,XY karyotype by conventional staining. External genitalia that range from ambiguous to normal female. Internal genitalia that range from absent müllerian structures to a fully developed uterus and fallopian tubes. Gonads that are characterized as normal testis, ovotestis, dysgenetic testis, or streak. Based on the particular features seen in any given individual, the clinical diagnosis may be designated as 46,XY disorder of sex development (DSD) or 46,XY complete gonadal dysgenesis (CDG).
Last Evaluated: Jun 26, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:56872885
Benign
Hetero
Gene:
GALNS
Variant:
c.758+22C>T
rsID: rs78317153
Ref Allele: G
Alt Allele: A
Freq: 4.7942%uncommon
CADD: 0.326
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 24, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:88835703
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 24, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:88835703
Benign
Hetero
Gene:
SPINK5
Variant:
c.209+15C>T
rsID: rs3752677
Ref Allele: C
Alt Allele: T
Freq: 4.8054%uncommon
CADD: 1.328
ClinVar Submissions (2)
Netherton syndrome is a rare and severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Generalized scaly erythroderma is apparent at or soon after birth and usually persists. Scalp hair is sparse and brittle with a characteristic 'bamboo' shape under light microscopic examination due to invagination of the distal part of the hair shaft to its proximal part. Atopic manifestations include eczema-like rashes, atopic dermatitis, pruritus, hay fever, angioedema, urticaria, high levels of IgE in the serum, and hypereosinophilia. Life-threatening complications are frequent during the neonatal period, including hypernatremic dehydration, hypothermia, extreme weight loss, bronchopneumonia, and sepsis. During childhood, failure to thrive is common as a result of malnutrition, metabolic disorders, chronic erythroderma, persistent cutaneous infections, or enteropathy (summary by Bitoun et al., 2002).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:148070465
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:148070465
Benign/Likely benign
Hetero
Gene:
PIK3CA
Variant:
c.1747-13T>C
rsID: rs41273619
Ref Allele: T
Alt Allele: C
Freq: 4.8468%uncommon
CADD: 14.97
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 06, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:179219558
Benign
Hetero
Gene:
TRIOBP
Variant:
c.1306G>A
(p.Asp436Asn)
rsID: rs75659869
Ref Allele: G
Alt Allele: A
Freq: 4.8946%uncommon
CADD: 8.328
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 09, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:37723862
Benign
Hetero
Gene:
DNAJB6
Variant:
c.176-20A>G
rsID: rs28377945
Ref Allele: A
Alt Allele: G
Freq: 4.8985%uncommon
CADD: 0.458
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 29, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:157366482
Benign
Hetero
Gene:
SLC4A1
Variant:
c.1323G>A
(p.Leu441=)
rsID: rs5017
Ref Allele: C
Alt Allele: T
Freq: 4.8985%uncommon
CADD: 14.09
ClinVar Submissions (3)
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:44257767
A condition of inadequate circulating red blood cells (ANEMIA) or insufficient HEMOGLOBIN due to premature destruction of red blood cells (ERYTHROCYTES).
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:44257767
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:44257767
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:44257767
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:44257767
Benign/Likely benign
Hetero
Gene:
SLC4A1
Variant:
c.*270G>A
rsID: rs5027
Ref Allele: C
Alt Allele: T
Freq: 4.9256%uncommon
CADD: 0.027
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:44250188
A condition of inadequate circulating red blood cells (ANEMIA) or insufficient HEMOGLOBIN due to premature destruction of red blood cells (ERYTHROCYTES).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:44250188
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:44250188
Likely benign
Hetero
Gene:
KIF21A
Variant:
c.3672G>T
(p.Glu1224Asp)
rsID: rs75223821
Ref Allele: C
Alt Allele: A
Freq: 4.9543%uncommon
CADD: 16.94
ClinVar Submissions (1)
Congenital fibrosis of the extraocular muscles (CFEOM) refers to at least eight genetically defined strabismus syndromes (CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, Tukel syndrome, and CFEOM3 with polymicrogyria) characterized by congenital non-progressive ophthalmoplegia (inability to move the eyes) with or without ptosis (droopy eyelids) affecting part or all of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpabrae superioris) and/or the trochlear nucleus and nerve (cranial nerve IV) and its innervated muscle (the superior oblique). In general, affected individuals have severe limitation of vertical gaze (usually upgaze) and variable limitation of horizontal gaze. Individuals with CFEOM frequently compensate for the ophthalmoplegia by maintaining abnormal head positions at rest and by moving their heads rather than their eyes to track objects. Individuals with CFEOM3A may also have intellectual disability, social disability, Kallmann syndrome, facial weakness, and vocal cord paralysis; and/or may develop a progressive sensorimotor axonal polyneuropathy. Individuals with Tukel syndrome also have postaxial oligodactyly or oligosyndactyly of the hands. Those with CFEOM3 with polymicrogyria also have microcephaly and intellectual disability.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:39319974
Benign
Hetero
Gene:
PKHD1
Variant:
c.8302+18A>G
rsID: rs12529717
Ref Allele: T
Alt Allele: C
Freq: 4.9615%uncommon
CADD: 0.317
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 04, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:51830843
Benign
Hetero
Gene:
GALNS
Variant:
c.898+25C>G
rsID: rs113936280
Ref Allele: G
Alt Allele: C
Freq: 4.9654%uncommon
CADD: 0.049
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 24, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:88835188
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 24, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:88835188
Benign
Hetero
Gene:
HPS1
Variant:
c.847G>T
(p.Gly283Trp)
rsID: rs11592273
Ref Allele: C
Alt Allele: A
Freq: 4.9678%uncommon
CADD: 3.192
ClinVar Submissions (4)
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:98429811
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:98429811
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:98429811
Benign/Likely benign
Hetero
Gene:
GALNS
Variant:
c.898+42G>C
rsID: rs76095307
Ref Allele: C
Alt Allele: G
Freq: 4.971%uncommon
CADD: 0.005
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:88835171
Benign
Hetero
Gene:
SLC2A1
Variant:
c.*1213G>T
rsID: rs55728431
Ref Allele: C
Alt Allele: A
Freq: 4.9734%uncommon
CADD: 6.337
ClinVar Submissions (1)
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:42925828
GLUT1 deficiency syndrome is a disorder affecting the nervous system that can have a variety of neurological signs and symptoms. Approximately 90 percent of affected individuals have a form of the disorder often referred to as common GLUT1 deficiency syndrome. These individuals generally have frequent seizures (epilepsy) beginning in the first months of life. In newborns, the first sign of the disorder may be involuntary eye movements that are rapid and irregular. Babies with common GLUT1 deficiency syndrome have a normal head size at birth, but growth of the brain and skull is often slow, which can result in an abnormally small head size (microcephaly). People with this form of GLUT1 deficiency syndrome may have developmental delay or intellectual disability. Most affected individuals also have other neurological problems, such as stiffness caused by abnormal tensing of the muscles (spasticity), difficulty in coordinating movements (ataxia), and speech difficulties (dysarthria). Some experience episodes of confusion, lack of energy (lethargy), headaches, or muscle twitches (myoclonus), particularly during periods without food (fasting).About 10 percent of individuals with GLUT1 deficiency syndrome have a form of the disorder often known as non-epileptic GLUT1 deficiency syndrome, which is usually less severe than the common form. People with the non-epileptic form do not have seizures, but they may still have developmental delay and intellectual disability. Most have movement problems such as ataxia or involuntary tensing of various muscles (dystonia); the movement problems may be more pronounced than in the common form.Several conditions that were originally given other names have since been recognized to be variants of GLUT1 deficiency syndrome. These include paroxysmal choreoathetosis with spasticity (dystonia 9); paroxysmal exercise-induced dyskinesia and epilepsy (dystonia 18); and certain types of epilepsy. In rare cases, people with variants of GLUT1 deficiency syndrome produce abnormal red blood cells and have uncommon forms of a blood condition known as anemia, which is characterized by a shortage of red blood cells.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:42925828
Benign
Hetero
Gene:
ATR
Variant:
c.3172-26T>A
rsID: rs76852171
Ref Allele: A
Alt Allele: T
Freq: 4.9758%uncommon
CADD: 0.004
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:142547936
Likely benign
Hetero
Gene:
SDHAF1
Variant:
c.333C>G
(p.Arg111=)
rsID: rs76336581
Ref Allele: C
Alt Allele: G
Freq: 4.9949%uncommon
CADD: 7.673
ClinVar Submissions (4)
Mitochondrial complex II deficiency is an autosomal recessive disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by Jain-Ghai et al., 2013).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35995607
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35995607
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35995607
Benign/Likely benign
Hetero