Submissions for variant NM_024422.6(DSC2):c.1039G>T (p.Asp347Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1214725211

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001188818	SCV001355962	uncertain significance	Cardiomyopathy	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 347 of the DSC2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001327618	SCV001518702	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2020-02-12	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with tyrosine at codon 347 of the DSC2 protein (p.Asp347Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSC2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx	RCV001547824	SCV001767618	uncertain significance	not provided	2020-01-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
All of Us Research Program, National Institutes of Health	RCV004010314	SCV004816183	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 347 of the DSC2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 not been identified 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.