Submissions for variant NM_024422.6(DSC2):c.1231A>G (p.Lys411Glu)

gnomAD frequency: 0.00002  dbSNP: rs560482778

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181149	SCV000233426	uncertain significance	not provided	2018-11-29	criteria provided, single submitter	clinical testing	The K411E variant of uncertain significance in the DSC2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 13/276812 (0.005%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the K411E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000812062	SCV000952364	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 411 of the DSC2 protein (p.Lys411Glu). This variant is present in population databases (rs560482778, gnomAD 0.02%). 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: 199766). 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. 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	RCV001189655	SCV001356986	uncertain significance	Cardiomyopathy	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 411 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 DSC2-related disorders in the literature. This variant has been identified in 13/282332 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	RCV003380505	SCV004097115	likely benign	Cardiovascular phenotype	2023-06-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV003996598	SCV004816171	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 411 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 13/282332 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.