ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2389G>A (p.Gly797Arg) (rs200121281)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590785 SCV000573405 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The G797R variant has not been published as pathogenic or been reported as benign to our knowledge. The G797R variant is observed in 16/24016 (0.07%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The G797R 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. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, G797R 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).
Integrated Genetics/Laboratory Corporation of America RCV000590785 SCV000697615 likely benign not provided 2017-03-06 criteria provided, single submitter clinical testing Variant summary: The RYR2 c.2389G>A (p.Gly797Arg) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 7/120662 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000715 (7/9794). This frequency is about 29 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance, without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.
Invitae RCV000639111 SCV000760672 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-10-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 797 of the RYR2 protein (p.Gly797Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs200121281, ExAC 0.07%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 180488). 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.
Blueprint Genetics RCV000157447 SCV000207191 uncertain significance Long QT syndrome 2014-11-25 no assertion criteria provided clinical testing

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