ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.5923A>G (p.Met1975Val) (rs200318013)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171678 SCV000055285 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171678 SCV000235124 uncertain significance not provided 2014-04-04 criteria provided, single submitter clinical testing p.Met1975Val (ATG>GTG): c.5923 A>G in exon 39 of the RYR2 gene (NM_001035.2). The M1975V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The M1975V variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. However, the M1975V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis predicts this variant likely does not alter the protein structure/function. Missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in ARRHYTHMIA panel(s).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212981 SCV000272395 uncertain significance not specified 2016-02-10 criteria provided, single submitter clinical testing The p.Met1975Val variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 6/66168 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s200318013). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Met1975Val variant is uncertain.

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