Submissions for variant NM_024422.6(DSC2):c.2318G>C (p.Gly773Ala)

gnomAD frequency: 0.00001  dbSNP: rs749174176

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181163	SCV000233440	uncertain significance	not provided	2020-10-09	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; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 199773; Landrum et al., 2016)
Invitae	RCV000526044	SCV000645008	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 773 of the DSC2 protein (p.Gly773Ala). This variant is present in population databases (rs749174176, gnomAD 0.003%). 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: 199773). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV001189656	SCV001356987	uncertain significance	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 773 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 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.
Fulgent Genetics, Fulgent Genetics	RCV000526044	SCV002782544	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-08-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165380	SCV003853631	uncertain significance	Cardiovascular phenotype	2023-03-05	criteria provided, single submitter	clinical testing	The p.G773A variant (also known as c.2318G>C), located in coding exon 15 of the DSC2 gene, results from a G to C substitution at nucleotide position 2318. The glycine at codon 773 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.