ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.754A>G (p.Ile252Val) (rs751996698)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000252744 SCV000319678 uncertain significance Cardiovascular phenotype 2015-05-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000644639 SCV000766342 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-07-23 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 252 of the DSC2 protein (p.Ile252Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs751996698, ExAC 0.01%). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 264041). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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