Submissions for variant NM_001943.5(DSG2):c.1912G>A (p.Gly638Arg)

gnomAD frequency: 0.00016  dbSNP: rs201564919

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154703	SCV000204382	uncertain significance	not specified	2016-11-07	criteria provided, single submitter	clinical testing	The p.Gly638Arg variant in DSG2 has been identified in 1 Caucasian individual wi th HCM (LMM data) and at least 1 Caucasian individual with ARVC/D (De Bortoli 2 010, Rigato 2013). Although the variant segregated with disease in one affected sibling, it was also identified in 2 apparently unaffected older siblings (De Bo rtoli 2010, Rigato 2013). This variant has been identified in 14/66666 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs201564919). Computational prediction tools and conservation analy sis suggest that the p.Gly638Arg variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. In summary, the cl inical significance of the p.Gly638Arg variant is uncertain.
GeneDx	RCV000766866	SCV000233506	uncertain significance	not provided	2022-10-21	criteria provided, single submitter	clinical testing	Reported in conjunction with additional cardiogenetic variants in individuals with ARVC or sudden death (De Bortoli et al., 2010; Bauce et al., 2011; Rigato et al., 2013; Sanchez et al., 2016; El-Battrawy et al., 2018); Identified in a patient with Brugada syndrome in published literature (Di Resta et al., 2015); Identified independently and in conjunction with additional variants in individuals referred for cardiac genetic testing at GeneDx; segregation data is limited at this time; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24070718, 23299917, 21723241, 27930701, 29566126, 33803477, 34300226, 32050722, 20197793, 31402444, 26220970)
Invitae	RCV000539539	SCV000641967	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 638 of the DSG2 protein (p.Gly638Arg). This variant is present in population databases (rs201564919, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 20197793, 26220970, 27930701, 35819174). ClinVar contains an entry for this variant (Variation ID: 161224). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000619011	SCV000737779	likely benign	Cardiovascular phenotype	2022-01-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170377	SCV001332952	uncertain significance	Cardiomyopathy	2019-05-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170377	SCV001350806	uncertain significance	Cardiomyopathy	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 638 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant was reported in one individual affected with arrhythmogenic right ventricular cardiomyopathy and in three unaffected individuals from a family (PMID: 20197793) and an individual affected with sudden death (PMID: 27930701). It has been shown that this variant segregates with disease in four related individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29566126). Cardiomyocytes from one of these heterozygous carriers have shown ion channel dysfunctions and abnormal cellular electrophysiology as well as enhanced sensitivity to adrenergic stimulation (PMID: 29566126). This variant has also been identified in 33/280710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002492540	SCV002797675	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-08-27	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148474	SCV000190175	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2014-06-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766866	SCV001740923	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000766866	SCV001918954	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766866	SCV001932557	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766866	SCV001952498	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766866	SCV001968852	uncertain significance	not provided		no assertion criteria provided	clinical testing