ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1775C>T (p.Ala592Val) (rs140232809)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150521 SCV000197716 uncertain significance not specified 2014-07-03 criteria provided, single submitter clinical testing The Ala592Val variant in DSC2 has been reported in 1 adult with DCM (Elliott 201 0). However, it has also been identified in 1 adult healthy control (Kapplinger 2010) and in 0.1% (6/4406) of African American chromosomes screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs140232809) . Computational prediction tools and conservation analysis suggest that this var iant may not impact the protein, though this information is not predictive enoug h to rule out pathogenicity. In summary, the clinical significance of the Ala592 Val variant is uncertain.
GeneDx RCV000150521 SCV000233433 uncertain significance not specified 2014-12-19 criteria provided, single submitter clinical testing p.Ala592Val (GCG>GTG): c.1775 C>T in exon 12 of the DSC2 gene (NM_024422.3). The Ala592Val variant in the DSC2 gene has been reported in one patient with dilated cardiomyopathy (DCM) and it was classified as a variant of unknown significance (Elliott P et al., 2010). Ala592Val results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is not well conserved across species. In silico analysis predicts Ala592Val is benign to the protein structure/function. The NHLBI Exome Sequencing Project and 1,000 Genomes project identified the Ala592Val variant with a frequency of 0.1-0.4% in individuals of African American ancestry. Kapplinger et al. also reported Ala592Val in 1/427 healthy control subjects. However, mutations in a nearby codon (Ile603Thr, Ile603Leu) have been reported in association with ARVC, supporting the functional importance of this region of the protein. With the clinical and molecular information available at this time, we cannot definitively determine if Ala592Val is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV000459183 SCV000561689 likely benign not provided 2019-02-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618922 SCV000735741 likely benign Cardiovascular phenotype 2017-01-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)

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