ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1172C>A (p.Ala391Asp)

gnomAD frequency: 0.00001  dbSNP: rs1300215880
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001361264 SCV001557233 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2022-06-30 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 666379). 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 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 391 of the DSC2 protein (p.Ala391Asp).
Ambry Genetics RCV002332726 SCV002631040 uncertain significance Cardiovascular phenotype 2020-08-20 criteria provided, single submitter clinical testing The p.A391D variant (also known as c.1172C>A), located in coding exon 9 of the DSC2 gene, results from a C to A substitution at nucleotide position 1172. The alanine at codon 391 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant co-occurred with a second DSC2 variant in a primary electrical disease cohort; however, detail was limited (Proost D et al. J Mol Diagn, 2017 05;19:445-459). 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.
Color Diagnostics, LLC DBA Color Health RCV003532283 SCV004363099 uncertain significance Cardiomyopathy 2022-11-06 criteria provided, single submitter clinical testing This missense variant replaces alanine with aspartic acid at codon 391 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 DSC2-related disorders in the literature. This variant has been identified in 2/282540 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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