ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13325C>T (p.Ala4442Val) (rs1553324230)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497562 SCV000589818 uncertain significance not provided 2018-09-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The A4442V variant has not been published as pathogenic or been reported as benign to our knowledge. The A4442V variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, A4442V is 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). Nevertheless, the A4442V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this variant has not been observed in a significant number of affected individuals and it lacks both segregation and functional studies which would further clarify its pathogenicity.

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