ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2716C>G (p.Pro906Ala) (rs754520058)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767109 SCV000621210 uncertain significance not provided 2017-09-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The P906A variant has been reported in one patient with hypertrophic cardiomyopathy (HCM) (Lopes et al., 2015); however, additional clinical details and segregation information were not provided. The P906A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P906A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved across species and where alanine (A) is present as the wild type in at least one species. Finally, the P906A variant 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).
Invitae RCV000813455 SCV000953815 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 906 of the RYR2 protein (p.Pro906Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs754520058, ExAC 0.01%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 229215). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000216388 SCV000272383 uncertain significance not specified 2015-04-29 criteria provided, single submitter clinical testing The p.Pro906Ala in RYR2 has not been previously reported in individuals with car diomyopathy, but has been identified in 1/64300 European chromosomes and in 1/95 00 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org). Proline at position 906 is poorly conserved in evolution with 7 fish species carrying the variant amino acid (alanine, Ala), suggesting that this change may be tolerated. On the other hand, this variant is located in the last three bases of the exon, which are part of the 5? splice region. Computatio nal tools raise the possibility of an impact to splicing, though this informatio n is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro906Ala variant is uncertain.

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