ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1051A>G (p.Ser351Gly) (rs139326669)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037260 SCV000060917 likely benign not specified 2012-04-25 criteria provided, single submitter clinical testing Ser351Gly in exon 9 of DSG2: This variant has been identified in 2 individuals w ith ARVC and was absent from 600 control chromosomes (Quarta 2011). However, thi s variant is not expected to have clinical significance because it is not locate d within the splice consensus sequence and has been identified in 0.6% (19/2964) of African American chromosomes from a broad, though clinically unspecified pop ulation (dbSNP rs139326669, NHLBI Exome Sequencing Project; http://evs.gs.washin gton.edu/EVS)
GeneDx RCV000037260 SCV000168236 benign not specified 2014-03-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000243296 SCV000318700 likely benign Cardiovascular phenotype 2019-01-09 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000477309 SCV000561383 benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-11-14 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770550 SCV000901997 likely benign Cardiomyopathy 2017-02-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000477309 SCV001283482 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-10-15 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Health, Inc RCV000770550 SCV001345833 benign Cardiomyopathy 2018-11-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037260 SCV001426910 benign not specified 2020-07-13 criteria provided, single submitter clinical testing Variant summary: DSG2 c.1051A>G (p.Ser351Gly) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 249292 control chromosomes, predominantly at a frequency of 0.0078 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 312-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1051A>G has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Pugh_2014, Quarta_2011). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile; Internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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