Submissions for variant NM_024422.6(DSC2):c.2357T>C (p.Met786Thr)

gnomAD frequency: 0.00001  dbSNP: rs397517398

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039418	SCV000063102	uncertain significance	not specified	2015-02-17	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Color Diagnostics, LLC DBA Color Health	RCV001178862	SCV001343415	uncertain significance	Cardiomyopathy	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 786 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 nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/276834 chromosomes (10/30782 South Asian 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.
All of Us Research Program, National Institutes of Health	RCV003996436	SCV004816062	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 786 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 nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/276834 chromosomes (10/30782 South Asian 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089368	SCV005772612	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 786 of the DSC2 protein (p.Met786Thr). This variant is present in population databases (rs397517398, gnomAD 0.03%). 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: 46177). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.