Submissions for variant NM_001943.5(DSG2):c.2759T>G (p.Val920Gly)

gnomAD frequency: 0.00439  dbSNP: rs142841727

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148473	SCV000051528	benign	Arrhythmogenic right ventricular cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037294	SCV000060951	likely benign	not specified	2015-08-21	criteria provided, single submitter	clinical testing	p.Val920Gly in exon 15 of DSG2: This variant has been reported in several indivi duals with ARVC or DCM but did not segregate with disease in one family member ( Syrris 2007, Posch 2008, Barahona-Dussault 2010, Christensen 2010). It has been identified in 0.5% (316/66608) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142841727). This freq uency strongly argues against a disease causing role but is too low to establish this with confidence.
Eurofins Ntd Llc (ga)	RCV000037294	SCV000226263	benign	not specified	2015-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000037294	SCV000233469	benign	not specified	2015-05-08	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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000148473	SCV000257908	benign	Arrhythmogenic right ventricular cardiomyopathy	2015-06-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000755252	SCV000287237	benign	Arrhythmogenic right ventricular dysplasia 10	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000245262	SCV000318981	benign	Cardiovascular phenotype	2017-02-08	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001701728	SCV000603385	benign	not provided	2023-08-07	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000037294	SCV000747997	benign	not specified	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776064	SCV000910712	benign	Cardiomyopathy	2018-04-08	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852745	SCV000995462	benign	Arrhythmogenic right ventricular cardiomyopathy; Cardiomyopathy	2018-05-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000755252	SCV001287045	likely benign	Arrhythmogenic right ventricular dysplasia 10	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776064	SCV002043142	benign	Cardiomyopathy	2020-03-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001701728	SCV002563458	likely benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	DSG2: BP4, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV001701728	SCV005215252	likely benign	not provided		criteria provided, single submitter	not provided
CSER _CC_NCGL, University of Washington	RCV000148473	SCV000190174	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000037294	SCV000280084	uncertain significance	not specified	2015-06-24	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We consider this variant to be of uncertain significance, likely benign, given it is present in multiple control samples and that it failed to segregate with disease in one family. This variant has been reported in 6 unrelated cases with either ARVC or DCM and as many as 6 total cases. Syrris et al (2006) initially identified the variant in a 17 yo male who had a sudden cardiac arrest, a left ventricular variant of ARVC was confirmed on autopsy. The proband’s father who had a positive phenotype on MRI and an abnormal signal average ECG was found to be genotype positive for the variant. Posch et al (2008) identified the variant in two families with dilated cardiomyopathy (note they refer to the variant as p.Val919Gly due to a numbering difference). However they report that the variant did not segregate with the phenotype in one family. In that family five affected relatives had the variant but one affected relative did not, indicating that it is likely not the primary causative variant of their disease. Christensen et al (2010) also reported the variant in 1 case that was clinically borderline for ARVC. Quarta et al (2011) found p.Val920Gly in 2 out of 100 families with ARVC. This is a conservative amino acid change with a nonpolar Valine replaced by a nonpolar Glyceine. SIFT predicts the amino acid change to be tolerated while PolyPhen predicts it to be probably damaging to the resulting protein. A variant in a nearby codon (p.Pro925Ser) has been reported in association with disease (University Medical Center Groningen ARVD/C Genetic Variants Database). Syrris et al (2006) reported that the variant was absent in 200 presumably healthy controls. Posch et al (2008) identified p.Val920Gly in 2 out of 432 presumably healthy control individuals. Christensen et al (2010) reported that the variant was present in 3 out of 650 individuals from a control population. Cox et al (2011) reported that the variant was absent in 200 controls. The variant is listed in dbSNP (rs142841727) with frequency data from the ClinSeq project, where it was seen in 8 of 660 individuals. It is listed in 1000Genomes, but only in reference to the dbSNP entry (as of April 17th, 2013). Additionally the variant was found in 41/4135 Caucasians and 6/1948 African American individuals in the NHLBI Exome Sequencing Project dataset (as of April 17th, 2013).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000037294	SCV001740980	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701728	SCV001930813	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000037294	SCV001970597	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037294	SCV001979185	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914935	SCV004728201	benign	DSG2-related disorder	2019-09-30	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).