ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1438A>C (p.Met480Leu)

gnomAD frequency: 0.00001  dbSNP: rs370616107
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000798386 SCV000938002 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2022-11-01 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: 644465). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 480 of the DSC2 protein (p.Met480Leu).
Color Diagnostics, LLC DBA Color Health RCV001186549 SCV001353010 uncertain significance Cardiomyopathy 2018-11-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the extracellular cadherin domain 4 of the DSC2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/30976 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Ambry Genetics RCV002388458 SCV002702871 uncertain significance Cardiovascular phenotype 2022-03-03 criteria provided, single submitter clinical testing The p.M480L variant (also known as c.1438A>C), located in coding exon 10 of the DSC2 gene, results from an A to C substitution at nucleotide position 1438. The methionine at codon 480 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. 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.

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