ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1241G>A (p.Arg414His)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001049625 SCV001213684 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 414 of the RYR2 protein (p.Arg414His). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
Illumina Clinical Services Laboratory,Illumina RCV001098556 SCV001254930 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001098557 SCV001254931 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color RCV001176534 SCV001340551 uncertain significance Cardiomyopathy 2019-07-16 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001249002 SCV001422846 uncertain significance not specified 2020-01-22 no assertion criteria provided curation The p.Arg414His variant in RYR2 has not been previously reported in individuals with catecholaminergic polymorphic ventricular tachycardia, CPVT, but has been identified in 0.005125% (1/19514) of East Asian chromosomes, 0.003268% (1/30602) of South Asian chromosomes, and 0.0007796% (1/128278) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs371121679). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for disease with incomplete penetrance. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population and CPVT is known to be incompletely penetrant (PMID: 20301466). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Two additional variants, resulting in a different amino acid change at the same position, p.Arg414Leu and p.Arg414Cys, have been reported in 2 individuals in association with unexplained drowning or near drowning due to suspected CPVT in the literature (PMID: 15466642, 15887426). The number of missense variants reported in RYR2 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP2 (Richards 2015).

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