ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1939C>T (p.Arg647Cys) (rs202040519)

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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 RCV000154813 SCV000204493 uncertain significance not specified 2013-04-03 criteria provided, single submitter clinical testing The Arg647Cys variant in RYR2 has not been reported in the literature nor previo usly identified by our laboratory. This variant has been identified in 1/8366 Eu ropean American chromosomes and 1/3992 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project ( EVS/; dbSNP rs202040519). Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. At this time, additional information is needed to fully assess the clinical significance of this variant.
GeneDx RCV000656970 SCV000565509 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The R647C variant has not been published as pathogenic or been reported as benign to our knowledge. The R647C variant is observed in 28/126458 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The R647C 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). Nevertheless, the R647C 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. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000619369 SCV000735564 uncertain significance Cardiovascular phenotype 2018-12-14 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000639113 SCV000760675 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 647 of the RYR2 protein (p.Arg647Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs202040519, ExAC 0.05%), 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: 178115). 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.
Color RCV000771900 SCV000904664 uncertain significance Cardiomyopathy 2019-11-14 criteria provided, single submitter clinical testing

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