Submissions for variant NM_024422.6(DSC2):c.595C>T (p.Arg199Cys)

gnomAD frequency: 0.00003  dbSNP: rs769787593

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000590953	SCV000700122	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Invitae	RCV000693817	SCV000822236	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-07-12	criteria provided, single submitter	clinical testing	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. 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 DSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 496660). This missense change has been observed in individual(s) with left ventricular non-compaction (PMID: 28798025). This variant is present in population databases (rs769787593, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 199 of the DSC2 protein (p.Arg199Cys).
Illumina Laboratory Services, Illumina	RCV000693817	SCV001282909	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2018-01-12	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.
Color Diagnostics, LLC DBA Color Health	RCV001179075	SCV001343660	uncertain significance	Cardiomyopathy	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 199 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 observed in an individual affected with left ventricular non-compaction (PMID: 28798025). This variant has been identified in 4/251394 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.
GeneDx	RCV001541214	SCV001759185	uncertain significance	not provided	2020-09-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 27054166, 28798025)
MGZ Medical Genetics Center	RCV000693817	SCV002581179	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-10-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002358651	SCV002656379	uncertain significance	Cardiovascular phenotype	2023-06-12	criteria provided, single submitter	clinical testing	The p.R199C variant (also known as c.595C>T), located in coding exon 5 of the DSC2 gene, results from a C to T substitution at nucleotide position 595. The arginine at codon 199 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a patient with hypertrophic cardiomyopathy and in a left ventricular non-compaction cohort; however clinical details were limited in the latter case (Bottillo I et al. Gene, 2016 Feb;577:227-35; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004002450	SCV004819336	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 199 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 observed in an individual affected with left ventricular non-compaction (PMID: 28798025). This variant has been identified in 4/251394 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.