Submissions for variant NM_024422.6(DSC2):c.2381C>T (p.Ser794Leu)

gnomAD frequency: 0.00002  dbSNP: rs1617629

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414169	SCV000491742	uncertain significance	not specified	2016-11-17	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSC2 gene. The S794L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the S794L 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. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000795744	SCV000935216	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 794 of the DSC2 protein (p.Ser794Leu). This variant is present in population databases (rs1617629, gnomAD 0.009%). 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: 373169). 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	RCV001191558	SCV001359420	likely benign	Cardiomyopathy	2018-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002450955	SCV002737045	likely benign	Cardiovascular phenotype	2020-07-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.