ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12944G>A (p.Gly4315Glu) (rs766109950)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522106 SCV000620408 uncertain significance not provided 2017-08-29 criteria provided, single submitter clinical testing The G4315E variant of uncertain significance in the RYR2 gene has previously been reported in one individual with either a CPVT or atypical LQTS phenotype and in one individual with sudden unexpected death during sleep (Medeiros-Domingo et al., 2009; Larsen et al., 2013). The G4315E variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G4315E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the G4315E variant 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). However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.

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