ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.977A>C (p.Gln326Pro) (rs397517409)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000039449 SCV000063133 uncertain significance not specified 2012-05-25 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Gln326Pro v ariant in DSC2 has not been reported in the literature and was not detected in 8 ,600 European American and 4,400 African American chromosomes screened by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). This variant h as been identified in 3 individuals (2 with ARVC, 1 with DCM) tested by our labo ratory. One individual (with ARVC) was homozygous (an affected family member was heterozygous) and another individual (with ARVC) carried another likely pathoge nic variant in the same gene. The individual with DCM carried a second, likely p athogenic variant in a DCM gene. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, absence from the ge neral population is consistent with pathogenicity; however, homozygosity in 1 in dividual and the presence of a second, likely pathogenic variant in another indi vidual raise some doubt as to whether this variant can cause disease. Additional studies are needed to fully assess its clinical significance.
Invitae RCV000696455 SCV000825018 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-04-12 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 326 of the DSC2 protein (p.Gln326Pro). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 46205). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.

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