Submissions for variant NM_024422.6(DSC2):c.1577C>T (p.Ser526Leu)

gnomAD frequency: 0.00001  dbSNP: rs887847751

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001761109	SCV001998679	uncertain significance	not provided	2019-09-04	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; This variant is associated with the following publications: (PMID: 31983221)
Ambry Genetics	RCV002405305	SCV002710071	uncertain significance	Cardiovascular phenotype	2021-07-23	criteria provided, single submitter	clinical testing	The p.S526L variant (also known as c.1577C>T), located in coding exon 11 of the DSC2 gene, results from a C to T substitution at nucleotide position 1577. The serine at codon 526 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Mazzarotto F et al. Circulation, 2020 02;141:387-398). This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. 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.
Invitae	RCV003517345	SCV004285444	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-03-20	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: 1311888). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). 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 526 of the DSC2 protein (p.Ser526Leu).
All of Us Research Program, National Institutes of Health	RCV004009017	SCV004829453	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 526 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 been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221). 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.