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

gnomAD frequency: 0.00246  dbSNP: rs139326669

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000477309	SCV000561383	benign	Arrhythmogenic right ventricular dysplasia 10	2024-01-29	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 Laboratory Services, Illumina	RCV000477309	SCV001283482	likely benign	Arrhythmogenic right ventricular dysplasia 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 Diagnostics, LLC DBA Color Health	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.
Fulgent Genetics, Fulgent Genetics	RCV002504890	SCV002807382	benign	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-07-27	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037260	SCV001919635	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701575	SCV001931391	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000037260	SCV001953041	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001701575	SCV001971269	likely benign	not provided		no assertion criteria provided	clinical testing