Submissions for variant NM_024422.6(DSC2):c.1057C>A (p.Pro353Thr)

gnomAD frequency: 0.00001  dbSNP: rs999869714

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469856	SCV000551490	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2025-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 353 of the DSC2 protein (p.Pro353Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 410653). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DSC2 protein function with a positive 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	RCV001525033	SCV001735029	uncertain significance	Cardiomyopathy	2024-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 353 of the DSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 25163546). This variant has been identified in 4/282462 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223214	SCV002501103	uncertain significance	not provided	2022-01-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298603	SCV002598951	uncertain significance	not specified	2024-07-10	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.1057C>A (p.Pro353Thr) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251060 control chromosomes, predominantly at a frequency of 2.6e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1057C>A has been reported in the literature in at least one individual affected with dilated cardiomyopathy (Haas_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 410653). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002411494	SCV002715634	uncertain significance	Cardiovascular phenotype	2022-02-16	criteria provided, single submitter	clinical testing	The p.P353T variant (also known as c.1057C>A), located in coding exon 8 of the DSC2 gene, results from a C to A substitution at nucleotide position 1057. The proline at codon 353 is replaced by threonine, an amino acid with highly similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort (Haas J et al. Eur Heart J, 2015 May;36:1123-35a). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004001866	SCV004816180	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 353 of the DSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 25163546). This variant has been identified in 4/282462 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.