ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8414G>A (p.Arg2805His) (rs1247067433)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520062 SCV000622093 uncertain significance not provided 2017-11-10 criteria provided, single submitter clinical testing The R2805H variant has not been published as pathogenic or been reported as benign to our knowledge. The R2805H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the R2805H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Color RCV000772058 SCV000905086 uncertain significance Cardiomyopathy 2018-10-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic 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 RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/146096 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV001212561 SCV001384149 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2805 of the RYR2 protein (p.Arg2805His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 453215). 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.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV001254774 SCV001430876 uncertain significance Sudden cardiac arrest 2020-04-07 no assertion criteria provided research This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us.

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