ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12047T>A (p.Phe4016Tyr) (rs375021201)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036670 SCV000060325 uncertain significance not specified 2012-11-14 criteria provided, single submitter clinical testing The Phe4016Tyr variant in RYR2 has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 1/8198 E uropean American chromosomes from a broad population screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Computational analyses ( biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summa ry, additional information is needed to fully assess the clinical significance o f the Phe4016Tyr variant.
GeneDx RCV000766732 SCV000235192 uncertain significance not provided 2017-10-20 criteria provided, single submitter clinical testing The F4016Y variant has not been published as pathogenic or been reported as benign to our knowledge. The F4016Y 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 across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The F4016Y 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). Though, F4016Y was observed in 22/125,516 (0.02%) alleles from individuals of European (Non-Finnish) from large population cohorts (Lek et al., 2016).
Illumina Clinical Services Laboratory,Illumina RCV000378772 SCV000356449 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000279641 SCV000356450 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000279641 SCV000955682 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with tyrosine at codon 4016 of the RYR2 protein (p.Phe4016Tyr). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and tyrosine. This variant is present in population databases (rs375021201, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 43718). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.

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