Submissions for variant NM_024422.6(DSC2):c.2587G>A (p.Gly863Arg)

gnomAD frequency: 0.00023  dbSNP: rs147109895

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039426	SCV000063110	uncertain significance	not specified	2016-03-06	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Gly863Arg var iant has been reported in the literature in one individual with DCM and 1 indivi dual with ARVC (Elliott 2010, Cox 2011). This variant has been identified in 0.0 3% (33/121305) of chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs147109895). Computational prediction tools and conservation analysis suggest that the p.Gly863Arg variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, its f requency suggests that it is more likely to be benign.
GeneDx	RCV000756035	SCV000233445	uncertain significance	not provided	2023-05-17	criteria provided, single submitter	clinical testing	Identified in multiple individuals with ARVC referred for genetic testing at GeneDx and in published literature (Cox et al., 2011; Kapplinger et al., 2011; Bhonsale et al. 2013; Proost et al., 2017; Ye et al., 2019; Vallverdu-Prats et al., 2021); many of these individuals also harbored different pathogenic variants in other ARVC-related genes; Reported in a patient with DCM and in a patient with ventricular fibrillation (Haas et al., 2015; Leinonen et al., 2018); 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: 23671136, 28341588, 28471438, 23911551, 23299917, 21636032, 20716751, 29032884, 31402444, 25163546, 33652588, 21606396)
Invitae	RCV000227283	SCV000290734	likely benign	Arrhythmogenic right ventricular dysplasia 11	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000246287	SCV000320415	likely benign	Cardiovascular phenotype	2021-09-23	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756035	SCV000883740	uncertain significance	not provided	2017-08-14	criteria provided, single submitter	clinical testing	The c.2587G>A; p.Gly863Arg variant (rs147109895) was observed in both patient and control individuals assessed for dilated cardiomyopathy (Elliott, 2010). In addition the p.Gly863Arg variant was reported in one patient analyzed for arrhythmogenic right ventricular dysplasia/cardiomyopathy, whom also carried a frameshift PKP2 allele associated with this disease (Cox, 2011). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.06 percent in the South Asian population (identified on 19 out of 30,770 chromosomes), and is listed in the ClinVar database with uncertain significance (Variation ID: 46183). The glycine at position 863 is highly conserved and computational analyses of the p.Gly863Arg variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Gly863Arg variant with certainty.
Color Diagnostics, LLC DBA Color Health	RCV000776155	SCV000911158	uncertain significance	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 863 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy, in two individuals affected with arrhythmogenic cardiomyopathy, in an individual suspected to be affected with hypertrophic cardiomyopathy, and in an individual who experienced a idiopathic ventricular fibrillation event (PMID: 20716751, 28341588, 29032884, 30847666, 33652588). This variant has also been reported in another individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic variant in the PKP2 gene (PMID: 21606396) and in an individual suspected to be affected with dilated cardiomyopathy who also carried a pathogenic variant in the SCN5A gene (PMID: 30847666). This variant has been identified in 74/282526 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for DSC2-related disorders, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039426	SCV000919279	uncertain significance	not specified	2017-09-05	criteria provided, single submitter	clinical testing	Variant summary: The DSC2 c.2587G>A (p.Gly863Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have not been confirmed by any in vitro/vivo functional studies. This variant was found in 34/122138 control chromosomes at a frequency of 0.0002784, which is approximately 28 times the estimated maximal expected allele frequency of a pathogenic DSC2 variant (0.00001), suggesting this variant is likely a benign polymorphism. This variant has been reported in affected individuals with DCM or ARVD. One ARVD patient also carried PKP2 variant c.917_918delCC, suggesting variant of interest may not be the primary cause of the phenotype. However, since ARVD is a known clinical entity that sometimes follows a digenic inheritance, we cannot exclude the pathogenicy of variant of interest based on the co-occurrence of PKP2 variant c.917_918delCC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign unitl more information becomes available.
Illumina Laboratory Services, Illumina	RCV000227283	SCV001281593	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
All of Us Research Program, National Institutes of Health	RCV003996440	SCV004823886	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 863 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy, in two individuals affected with arrhythmogenic cardiomyopathy, in an individual suspected to be affected with hypertrophic cardiomyopathy, and in an individual who experienced a idiopathic ventricular fibrillation event (PMID: 20716751, 28341588, 29032884, 30847666, 33652588). This variant has also been reported in another individual affected with arrhythmogenic right ventricular cardiomyopathy who also carried a pathogenic variant in the PKP2 gene (PMID: 21606396) and in an individual suspected to be affected with dilated cardiomyopathy who also carried a pathogenic variant in the SCN5A gene (PMID: 30847666). This variant has been identified in 74/282526 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for DSC2-related disorders, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000227283	SCV000536730	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2015-07-30	no assertion criteria provided	research
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000039426	SCV000804865	uncertain significance	not specified	2016-09-23	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000756035	SCV000925065	uncertain significance	not provided	2017-03-07	no assertion criteria provided	provider interpretation