Submissions for variant NM_024422.6(DSC2):c.658G>A (p.Gly220Arg)

gnomAD frequency: 0.00002  dbSNP: rs750961818

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001189549	SCV001356859	uncertain significance	Cardiomyopathy	2019-05-07	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 220 of the DSC2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals affected arrhythmogenic right ventricular cardiomyopathy (PMID: 20857253, 28588093). This variant has also been identified in 2/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Ambry Genetics	RCV002375101	SCV002667609	uncertain significance	Cardiovascular phenotype	2024-04-11	criteria provided, single submitter	clinical testing	The p.G220R variant (also known as c.658G>A), located in coding exon 6 of the DSC2 gene, results from a G to A substitution at nucleotide position 658. The glycine at codon 220 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported several times in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) cohorts, but clinical details were limited and the study cohorts overlapped (Tan BY et al. J Cardiovasc Transl Res. 2010;3:663-73; Bhonsale A et al. Circ Arrhythm Electrophysiol. 2013;6:569-78; te Riele AS et al. J. Am. Coll. Cardiol. 2013;62:1761-9; Groeneweg JA et al. Circ Cardiovasc Genet. 2015;8:437-46). This amino acid position is highly conserved in available vertebrate species; however, arginine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002484034	SCV002784031	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-08-03	criteria provided, single submitter	clinical testing
Invitae	RCV002484034	SCV003007768	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-12-24	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 926742). This missense change has been observed in individual(s) with clinical features of DSC2-related conditions (PMID: 20857253). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 220 of the DSC2 protein (p.Gly220Arg).
Revvity Omics, Revvity	RCV002484034	SCV003829123	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2020-12-10	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002484034	SCV003919887	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-03-30	criteria provided, single submitter	clinical testing	DSC2 NM_024422.4 exon 6 p.Gly220Arg (c.658G>A): This variant has been reported in the literature in at least 1 individual with a clinical suspicion of ARVC (Tan 2010 PMID:20857253, Te Riele 2013 PMID:23810894). This variant is present in 1/8728 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs750961818). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV004010365	SCV004819330	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 220 of the DSC2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals affected arrhythmogenic right ventricular cardiomyopathy (PMID: 20857253, 28588093). This variant has also been identified in 2/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.