Submissions for variant NM_024422.6(DSC2):c.548G>A (p.Arg183Gln)

dbSNP: rs554713834

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644629	SCV000766331	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 183 of the DSC2 protein (p.Arg183Gln). This variant is present in population databases (rs554713834, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 536264). 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 with a negative predictive value of 80%. 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	RCV000773296	SCV000906988	uncertain significance	Cardiomyopathy	2020-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 183 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251338 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	RCV004807065	SCV005427513	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 183 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251338 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358041	SCV001553680	uncertain significance	not provided		no assertion criteria provided	clinical testing	The DSC2 p.Arg183Gln variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs554713834), ClinVar (classified as a VUS by Invitae for Arrhythmogenic right ventricular cardiomyopathy, type 11) and Cosmic (predicted neutral by FATHMM; score=0.02). The variant was also identified in control databases in 1 of 251338 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: South Asian in 1 of 30612 chromosomes (freq: 0.000033); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), and Other populations. The p.Arg183 residue is not conserved in mammals and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.