ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4990G>T (p.Val1664Phe) (rs749434532)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766717 SCV000235114 uncertain significance not provided 2016-01-25 criteria provided, single submitter clinical testing The V1664F variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The V1664F variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V1664F variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, V1664F is not located in the hot-spot" regions of the RYR2 gene (Medeiros-Domingo A et al., 2009), and no missense mutations in nearby residues have been reported in association with RYR2-related disorder, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant."
Invitae RCV000702990 SCV000831868 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 1664 of the RYR2 protein (p.Val1664Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs749434532, ExAC 0.001%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201253). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000182730 SCV000272390 uncertain significance not specified 2015-04-10 criteria provided, single submitter clinical testing The p.Val1664Phe variant in RYR2 has not been previously identified in individua ls with cardiomyopathy, but has been identified in 1/66670 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Comp utational prediction tools and conservation analysis suggest that this variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. In summary, the clinical significance of the p.Val1664Phe va riant is uncertain.

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