ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.815G>T (p.Arg272Leu) (rs377368967)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618097 SCV000737790 uncertain significance Cardiovascular phenotype 2016-11-11 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000687476 SCV000815043 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-01-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 272 of the RYR2 protein (p.Arg272Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs377368967, ExAC 0.006%). This variant has not been reported in the literature in individuals with RYR2-related disease. 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.
Color RCV000772651 SCV000905910 uncertain significance Cardiomyopathy 2019-07-16 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001100221 SCV001256731 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001100222 SCV001256732 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Broad Institute Rare Disease Group,Broad Institute RCV001249072 SCV001423021 uncertain significance not specified 2020-01-22 no assertion criteria provided curation The p.Arg272Leu variant in RYR2 has not been previously reported in individuals with RYR2-related diseases but has been identified in 0.007793% (10/128322) of European (non-Finnish) chromosomes and 0.004133% (1/24196) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs377368967). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS in ClinVar (Variation ID: 519353). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant, resulting in a different amino acid change at the same position, p.Arg272His, has been reported as a VUS in association with disease in ClinVar (Variation ID: 618352). 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, PP3 (Richards 2015).

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