ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12919C>T (p.Arg4307Cys) (rs200092869)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171768 SCV000055292 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171768 SCV000235215 uncertain significance not provided 2018-10-23 criteria provided, single submitter clinical testing The R4307C variant of uncertain significance in the RYR2 gene has been reported in an individual with sudden unexplained death (Sanchez et al., 2016). In addition, R4307C has been described as a polymorphism (Medeiros-Domingo et al., 2009) and has been identified in two alleles from a cohort of individuals not selected for a history of arrhythmia, cardiomyopathy, or a family history of sudden cardiac death (Ng et al., 2013). This variant has also been identified in other unrelated individuals referred for cardiac genetic testing at GeneDx; however, the majority harbored additional cardiogenetic variants, and segregation data are uninformative thus far. This variant is observed in 74/126,242 (0.06%) alleles from individuals of European (non-Finnish) background in large population cohorts, including one homozygous individual (Lek et al., 2016). Nevertheless, R4307C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, R4307C 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).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212983 SCV000272377 uncertain significance not specified 2015-07-30 criteria provided, single submitter clinical testing The p.Arg4307Cys variant in RYR2 has been reported in the literature once withou t additional information (Medeiros-Domingo 2009). It has been identified in 22/6 6676 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac; dbSNP rs200092869). Computational prediction tools and cons ervation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg4307Cys variant is un certain.
Invitae RCV000531448 SCV000637504 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 4307 of the RYR2 protein (p.Arg4307Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200092869, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant was reported in an individual that suffered a sudden unexplained death (PMID: 27930701) and was also reported as a polymorphism in an individual from a long QT study (PMID: 19926015). ClinVar contains an entry for this variant (Variation ID: 191546). 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.
Ambry Genetics RCV000618657 SCV000738174 uncertain significance Cardiovascular phenotype 2017-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000776390 SCV000911854 uncertain significance Cardiomyopathy 2018-04-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant in the RYR2 protein and is not associated with a known functional domain. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant was reported in an individual that suffered a sudden unexplained death (PMID: 27930701). This variant has been identified in 86/276644 (1 homozygote) chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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