ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1597G>A (p.Val533Ile) (rs199761749)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000236942 SCV000294290 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621353 SCV000738127 likely benign Cardiovascular phenotype 2017-08-04 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Color Health, Inc RCV000776129 SCV000911070 benign Cardiomyopathy 2018-04-13 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000236942 SCV001286955 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193023 SCV001361556 likely benign not specified 2019-11-18 criteria provided, single submitter clinical testing Variant summary: DSG2 c.1597G>A (p.Val533Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 249320 control chromosomes, predominantly at a frequency of 0.0023 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 230-fold the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1597G>A has been reported in the literature in individuals affected with arrhythmogenic right ventricular cadiomyopathy and dilated cardiomyopathy without strong evidence for causality (Shestak_2014, Wada_2017, Dai_2019) . These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) have cited the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV001550698 SCV001771072 likely benign not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 29178656)

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