Submissions for variant NM_024422.6(DSC2):c.2328C>G (p.Ile776Met)

gnomAD frequency: 0.00001  dbSNP: rs1789054

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000618344	SCV000736920	uncertain significance	Cardiovascular phenotype	2023-06-02	criteria provided, single submitter	clinical testing	The p.I776M variant (also known as c.2328C>G), located in coding exon 15 of the DSC2 gene, results from a C to G substitution at nucleotide position 2328. The isoleucine at codon 776 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000604239	SCV000744756	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2017-10-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000604239	SCV001211053	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 776 of the DSC2 protein (p.Ile776Met). This variant is present in population databases (rs1789054, 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: 518278). 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	RCV001181570	SCV001346747	uncertain significance	Cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 776 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 hypertrophic cardiomyopathy (PMID: 26656175). This variant has been identified in 4/251132 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000604239	SCV003919886	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-03-30	criteria provided, single submitter	clinical testing	DSC2 NM_024422.6 exon 15 p.Ile776Met (c.2328C>G): This variant has not been reported in the literature but is present in 0.003% (4/113454) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/18-28649040-G-C). This variant is present in ClinVar (Variation ID:518278). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV004002635	SCV004816067	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 776 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 cardiovascular disorders in the literature. This variant has been identified in 4/251132 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000604239	SCV000733773	uncertain significance	Arrhythmogenic right ventricular dysplasia 11		no assertion criteria provided	clinical testing