ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2104G>A (p.Gly702Arg) (rs569386030)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156219 SCV000205935 uncertain significance not specified 2013-12-12 criteria provided, single submitter clinical testing The Gly702Arg variant in RYR2 has not been reported in individuals with cardiomy opathy or in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. Additional information is needed to fully assess the clinical significance of this variant.
Color RCV000771901 SCV000904665 uncertain significance Cardiomyopathy 2018-06-18 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the cytoplasmic SPRY domain of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact 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 nor has the variant been reported in individuals affected with cardiovascular disease in the literature. This variant is rare in the general population and has been identified in 18/30780 South Asian chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000801689 SCV000941479 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 702 of the RYR2 protein (p.Gly702Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs569386030, ExAC 0.03%). This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 179430). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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