Submissions for variant NM_024422.6(DSC2):c.394C>T (p.Arg132Cys)

gnomAD frequency: 0.00002  dbSNP: rs727504578

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155749	SCV000205460	uncertain significance	not specified	2018-10-24	criteria provided, single submitter	clinical testing	The p.Arg132Cys variant in DSC2 has been identified in 3 individuals with ARVC, one of whom carried a likely pathogenic variant in PKP2 and another of whom also carried a frameshift variant in DSC2 (Fressart 2010, Ohno 2013, Wada 2017, LMM data). This variant has been identified in 10/282564 chromosomes by the gnomAD ( http://gnomad.broadinstitute.org). Computational prediction tools and conservati on analysis suggest that the p.Arg132Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary , the clinical significance of the p.Arg132Cys variant is uncertain. ACMG/AMP Cr iteria applied: PP3.
Invitae	RCV000230389	SCV000290741	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 132 of the DSC2 protein (p.Arg132Cys). This variant is present in population databases (rs727504578, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 23514727, 33784018). ClinVar contains an entry for this variant (Variation ID: 178972). 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 expected to disrupt DSC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DSC2 function (PMID: 33784018). 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.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001089601	SCV001245073	uncertain significance	Aborted sudden cardiac death	2018-07-26	criteria provided, single submitter	research	DSC2 Arg132Cys has been reported previously in 2 ARVC patients, however both patients also had other DSC2 variants (Fressart V et al., 2010; Ohno S, et al., 2013). We have identified this variant in a proband of south-east asian descent whom presented with cardiac arrest. The patient was also found to have a second variant (PKP2 p.Leu744Serfs*3). Clinical screening did not uncover any abnormal findings, but it is possible that the patient may have a 'concealed' ARVC phenotype. The proband has no family history of any inherited cardiac disease or sudden death. The variant is present at an elevated frequency in the Genome Aggregation Database (MAF= 0.000036, http://gnomad.broadinstitute.org/). In silico tools SIFT, MutationTaster, CADD and PolyPhen-2 all predict the variant to be deleterious. In summary, the variant has been reported in at least 3 probands with multiple variants, it is present in population databases but is still considered rare and in silico tools predict it to be deleterious, therefore based on this conflicting information we classify DSC2 Arg132Cys as a variant of 'uncertain significance'.
Ambry Genetics	RCV002354373	SCV002621025	uncertain significance	Cardiovascular phenotype	2019-05-01	criteria provided, single submitter	clinical testing	The p.R132C variant (also known as c.394C>T), located in coding exon 4 of the DSC2 gene, results from a C to T substitution at nucleotide position 394. The arginine at codon 132 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), who also had additional cardiac-related variants detected (Fressart V et al. Europace, 2010 Jun;12:861-8; Ohno S et al. Circ. J., 2013 Mar;77:1534-42). This alteration has also been seen in an exome cohort, but detailed cardiovascular history was not provided (Haggerty CM et al. Genet. Med., 2017 11;19:1245-1252). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	RCV003319180	SCV003932396	uncertain significance	Primary dilated cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003531985	SCV004363123	uncertain significance	Cardiomyopathy	2022-12-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 132 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). A functional study has shown that, unlike wildtype, this variant can't rescue the cardiovascular phenotypes in DSC2 knockdown zebrafish model (PMID: 33784018). This variant has been reported in an individual affected with cardiac arrest (ClinVar SCV001245073.1) and in four unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 20400443, 23514727, 29178656, 33784018, ClinVar SCV000205460.4). Two of these probands also carried a truncating variant in DSC2 or PKP2 genes (PMID: 20400443, ClinVar SCV001245073.1). Studies with heart samples and cardiomyocytes derived from one of the probands revealed altered electric activity and a marked reduction of DSC2 in both mRNA and protein levels (PMID: 33784018, 35297182). This variant has been identified in 10/282564 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.
All of Us Research Program, National Institutes of Health	RCV003998289	SCV004819352	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 132 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). A functional study has shown that, unlike wildtype, this variant can't rescue the cardiovascular phenotypes in DSC2 knockdown zebrafish model (PMID: 33784018). This variant has been reported in an individual affected with cardiac arrest (ClinVar SCV001245073.1) and in four unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 20400443, 23514727, 29178656, 33784018, ClinVar SCV000205460.4). Two of these probands also carried a truncating variant in DSC2 or PKP2 genes (PMID: 20400443, ClinVar SCV001245073.1). Studies with heart samples and cardiomyocytes derived from one of the probands revealed altered electric activity and a marked reduction of DSC2 in both mRNA and protein levels (PMID: 33784018, 35297182). This variant has been identified in 10/282564 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000996663	SCV001743114	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000996663	SCV001956402	uncertain significance	not provided		no assertion criteria provided	clinical testing