ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13984G>A (p.Gly4662Ser) (rs886039213)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244610 SCV000320684 uncertain significance Cardiovascular phenotype 2015-12-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000481567 SCV000568210 uncertain significance not provided 2017-03-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The G4662S variant has been previously reported in at least one individual with CPVT (Postma et al., 2005; Hayashi et al., 2009). Postma et al. (2005) reported this variant in a French female with CPVT, who also harbored the H4762P variant in the RYR2 gene, and had a brother with sudden death at 20 years of age. Although familial testing was not completed in the deceased brother, the G4662S variant was paternally inherited, and the H4762P variant was maternally inherited and present in her two children, and these relatives were all clinically unaffected (Postma et al., 2005). Nevertheless, the G4662S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G4662S 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. Moreover, 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, G4662S 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 has not been observed in a significant number of affected individuals and it lacks large segregation studies and functional evidence, which would further clarify its role in disease. Finally, this variant is also classified in ClinVar as a variant of uncertain significance by a different clinical laboratory (ClinVar SCV000320684.1; Landrum et al., 2016).

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