ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8696A>G (p.Asn2899Ser) (rs1057524444)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000440473 SCV000535572 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The N2899S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N2899S variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, N2899S is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species, and Serine is the wild-type residue at this position in multiple mammalian species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly, N2899S is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009).

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