ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1996G>A (p.Val666Ile)

gnomAD frequency: 0.00001  dbSNP: rs758646191
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000644627 SCV000766329 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2017-10-15 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 do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DSC2-related disease. This variant is present in population databases (rs758646191, ExAC 0.01%). This sequence change replaces valine with isoleucine at codon 666 of the DSC2 protein (p.Val666Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine.
Ambry Genetics RCV002422332 SCV002717676 uncertain significance Cardiovascular phenotype 2021-07-16 criteria provided, single submitter clinical testing The p.V666I variant (also known as c.1996G>A), located in coding exon 13 of the DSC2 gene, results from a G to A substitution at nucleotide position 1996. The valine at codon 666 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, isoleucine 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.
All of Us Research Program, National Institutes of Health RCV004004054 SCV004819914 uncertain significance Familial isolated arrhythmogenic right ventricular dysplasia 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 666 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 2/250564 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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