ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.5096G>A (p.Arg1699His) (rs779464111)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182872 SCV000235260 uncertain significance not provided 2014-09-05 criteria provided, single submitter clinical testing p.Arg1699His (CGT>CAT): c.5096 G>A in exon 37 of the RYR2 gene (NM_001035.2). A variant of unknown significance has been identified in the RYR2 gene. The R1699H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1699H variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. 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. However, R1699H is located in a region of the RYR2 protein that contains few reported mutations and R1699H is not located in any of the three mutation hot spots" in the RYR2 gene (Medeiros-Domingo A et al., 2009). Additionally, the R1699H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This The variant is found in ARRHYTHMIA panel(s)."
Color RCV001179068 SCV001343650 uncertain significance Cardiomyopathy 2019-09-04 criteria provided, single submitter clinical testing
Invitae RCV001212328 SCV001383909 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-06-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1699 of the RYR2 protein (p.Arg1699His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs779464111, ExAC 0.003%). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201383). 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.

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