ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1024A>G (p.Ile342Val)

gnomAD frequency: 0.00001  dbSNP: rs746745677
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001992366 SCV002221187 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2023-09-23 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 342 of the DSC2 protein (p.Ile342Val). This variant is present in population databases (rs746745677, gnomAD 0.002%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20152563). ClinVar contains an entry for this variant (Variation ID: 1444476). 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.
Ambry Genetics RCV002386791 SCV002691532 uncertain significance Cardiovascular phenotype 2019-12-26 criteria provided, single submitter clinical testing The p.I342V variant (also known as c.1024A>G), located in coding exon 8 of the DSC2 gene, results from an A to G substitution at nucleotide position 1024. The isoleucine at codon 342 is replaced by valine, an amino acid with highly similar properties. This variant was reported in one individual from an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort; however, clinical details were limited (Xu T et al. J. Am. Coll. Cardiol., 2010 Feb;55:587-97). This amino acid position is not well conserved in available vertebrate species, and valine 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.
Color Diagnostics, LLC DBA Color Health RCV003533073 SCV004363103 uncertain significance Cardiomyopathy 2023-07-27 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 342 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 arrhythmogenic right ventricular cardiomyopathy (PMID: 20152563). This variant has been identified in 3/251052 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.

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