Submissions for variant NM_024422.6(DSC2):c.1352C>T (p.Ser451Leu)

dbSNP: rs794728068

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766858	SCV000233427	uncertain significance	not provided	2014-04-07	criteria provided, single submitter	clinical testing	p.Ser451Leu (TCA>TTA): c.1352 C>T in exon 10 of the DSC2 gene (NM_024422.3). A variant of unknown significance has been identified in the DSC2 gene. The S451L variant has not been published as a mutation or as a benign polymorphism to our knowledge. The S451L variant was not observed 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. The S451L 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. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with ARVC, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV002516830	SCV002993852	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-09-20	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 199767). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 451 of the DSC2 protein (p.Ser451Leu).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000181150	SCV000280075	uncertain significance	not specified	2015-09-16	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of population data, lack of case data, and the high prevalence of novel variants in these genes in the general population (reviewed below) we consider this variant a variant of uncertain significance. This gene has been associated with ARVC, including a left-sided phenotype. It has not, to our knowledge, been associated with HCM or LVNC. The variant is novel. In silico predictions are conflicting. This is a non-conservative amino acid change. The serine at codon 451 is not conserved across species. We could find no other variants at nearby codons and HGMD does not list any nearby disease-associated variants. In total the variant has not been seen in ~6500 individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals.