ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.11995A>G (p.Met3999Val) (rs794728780)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182805 SCV000235191 likely pathogenic not provided 2014-06-19 criteria provided, single submitter clinical testing p.Met3999Val (ATG>GTG): c.11995 A>G in exon 90 of the RYR2 gene (NM_001035.2). It has not been published as a mutation or as a benign polymorphism to our knowledge. The M3999V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the M3999V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. In addition, M3999V is located in a mutation hot spot within the channel region of the RYR2 gene (Medeiros-Domingo A et al., 2009). Furthermore, missense mutations in nearby residues (V3990D, K3997E, M4002I) have been reported in association with CPVT, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in CPVT,POSTMORTEM panel(s).

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