Submissions for variant NM_024422.6(DSC2):c.2335G>A (p.Gly779Arg)

gnomAD frequency: 0.00004  dbSNP: rs139290300

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171888	SCV000054841	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000171888	SCV000233441	uncertain significance	not provided	2014-06-25	criteria provided, single submitter	clinical testing	p.Gly779Arg (GGA>AGA): c.2335 G>A in exon 15 of the DSC2 gene (NM_024422.3) A variant of unknown significance has been identified in the DSC2 gene. The G779R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G779R variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The G779R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, mutations in nearby residues have not been reported in association with arrhythmia, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Eurofins Ntd Llc (ga)	RCV000171888	SCV000343580	uncertain significance	not provided	2016-07-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000171888	SCV000699498	uncertain significance	not provided	2016-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618174	SCV000737962	likely benign	Cardiovascular phenotype	2023-07-28	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	RCV000644646	SCV000766349	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-11-04	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 779 of the DSC2 protein (p.Gly779Arg). This variant is present in population databases (rs139290300, gnomAD 0.009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy (PMID: 25351510, 31737537). ClinVar contains an entry for this variant (Variation ID: 191619). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSC2 protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV000778022	SCV000914133	uncertain significance	Cardiomyopathy	2022-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 779 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 11/282502 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.
Illumina Laboratory Services, Illumina	RCV000644646	SCV001282798	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics, Fulgent Genetics	RCV000644646	SCV002816245	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-09-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995655	SCV004816066	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 779 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 11/282502 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.