ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.82G>T (p.Ala28Ser) (rs139979318)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246853 SCV000317822 uncertain significance Cardiovascular phenotype 2012-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000622276 SCV000740323 uncertain significance Familial dilated cardiomyopathy 2017-03-30 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223928 SCV000280080 uncertain significance not specified 2013-01-07 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we characterize this variant as a variant of uncertain significance. This variant has not been previously reported as a disease-causing mutation according to searches of PubMed and Google; it is present, however, in an African American population dataset. Variants in this gene can cause arrhythmogenic right ventricular cardiomyopathy (ARVC). This is a non-conservative amino acid change from a nonpolar alanine to a neutral, polar serine. It has a Grantham score of 99. The alanine at codon 28 is not well conserved across 30 vertebrate species examined (it is a serine in opossum, as in this patient, and a threonine in dog, kangaroo rat, and pika). In silico analysis with PolyPhen-2 (humVAR) predicts the variant to be “benign” with a score of 0.078; SIFT predicts it to be “tolerated” with a score of 0.830. In total this specific variant has been seen in 3 out of ~2500 African-American individuals from publicly available population datasets. It is present in 3/2203 African-American individuals in the NHLBI Exome Sequencing Project dataset, for an allele frequency of 0.07%. It was not present in 4300 European American individuals. This gives it an overall allele frequency in the ESP of 0.02%. It is present in dbSNP as rs139979318, submitted by the ESP. It is not present in 1000 genomes. (1000 genomes phase 1 is made up of 1092 individuals of various races, 246 of them with African or African-American ancestry). Presence of a variant among individuals in the general population cannot definitively rule it out as the cause of disease, as even gold-standard pathogenic cardiomyopathy variants have been found in population datasets (Pan et al. 2012).

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