Submissions for variant NM_024422.6(DSC2):c.1620C>G (p.Ile540Met)

dbSNP: rs765374888

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001178741	SCV001343253	uncertain significance	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 540 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251170 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.
Invitae	RCV002558888	SCV003457693	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-10-27	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: 920162). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is present in population databases (rs765374888, gnomAD 0.006%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 540 of the DSC2 protein (p.Ile540Met).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001178741	SCV003838117	uncertain significance	Cardiomyopathy	2022-03-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004006499	SCV004816144	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 540 of the DSC2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. 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 3/251170 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.
Ambry Genetics	RCV004033028	SCV005028652	benign	Cardiovascular phenotype	2023-12-12	criteria provided, single submitter	clinical testing	This alteration is classified as 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.