Submissions for variant NM_024422.6(DSC2):c.734A>C (p.Glu245Ala)

gnomAD frequency: 0.00013  dbSNP: rs373201722

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171895	SCV000050900	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000171895	SCV000517880	uncertain significance	not provided	2020-01-15	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 191624; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21636032)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644635	SCV000766338	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 245 of the DSC2 protein (p.Glu245Ala). This variant is present in population databases (rs373201722, 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: 191624). 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 tolerated. 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	RCV001187668	SCV001354527	uncertain significance	Cardiomyopathy	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 245 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 8/282338 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	RCV002381558	SCV002671099	benign	Cardiovascular phenotype	2021-09-21	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.
All of Us Research Program, National Institutes of Health	RCV003995659	SCV004816211	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 245 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 8/282338 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.