ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3038G>A (p.Arg1013Gln) (rs149514924)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619628 SCV000735621 likely benign Cardiovascular phenotype 2018-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,Other data supporting benign classification
CSER_CC_NCGL; University of Washington Medical Center RCV000148833 SCV000190574 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2014-06-01 no assertion criteria provided research
Color RCV000771801 SCV000904498 uncertain significance Cardiomyopathy 2018-05-21 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia or genotype-negative, exercise-induced long QT syndrome (PMID: 19926015), an individual affected with arrhythmogenic right ventricular cardiomyopathy (Ehdaie et al, 2017) and an individual with unexplained drowning (PMID: 21964171). However, this variant is fairly common in the general population and has been identified in 132/277112 chromosomes (115/126658 non-Finnish European chromosomes) by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589142 SCV000343218 uncertain significance not provided 2016-07-14 criteria provided, single submitter clinical testing
GeneDx RCV000589142 SCV000235087 uncertain significance not provided 2019-01-10 criteria provided, single submitter clinical testing The R1013Q variant of uncertain significance in the RYR2 gene has been published in association with variable cardiac phenotypes. Medeiros-Domingo et al. (2009) reported this variant in one individual from a cohort with either strong or possible CPVT or exercise-induced LQTS. This variant has also been identified in a 19 year-old victim of unexplained drowning (Tester et al., 2011), in an individual with a clinical diagnosis of ARVC (Avari et al., 2016), and in at least one individual with hypertrophic cardiomyopathy (Lopes et al., 2013; Lopes et al., 2015). Of note, Lopes et al. (2013) reported that this individual also harbored variants of uncertain significance in another gene. The R1013Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, the R1013Q variant 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). Finally, the R1013Q variant was observed in 115/126,658 (0.09%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Integrated Genetics/Laboratory Corporation of America RCV000589142 SCV000697620 benign not provided 2017-07-17 criteria provided, single submitter clinical testing Variant summary: The c.3038G>A (p.Arg1013Gln) in RYR2 gene is a missense change that involves the alteration of a mildly conserved nucleotide and 2/4 in silico tools predict benign outcome. The variant falls within one of the four RyR domains, however no functional studies confirming deleterious effect of the variant on the protein function were published at the time of evaluation. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00045 (55/120324 chrs tested), predominantly in individuals of European ancestry (0.00069; 46/66538 chrs tested). This frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.0000063). The pathogenicity of the variant was also questioned by recent reports (Olfson, 2015; Paludan-Mller, 2017), where authors indicate that prevalence of the variant in general population is higher than expected for the disorder. The variant was reported in at least one CPVT pt without strong evidence for causality. Lastly, several reputable databases/diagnostic centers classified the variant of interest as VUS. Taking together, based on the prevalence in general population the variant was classified as Benign.
Invitae RCV000233799 SCV000285719 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1013 of the RYR2 protein (p.Arg1013Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs149514924, ExAC 0.07%) This variant has been reported in an individual with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome, in one individual who drowned without explanation and in an individual with hypertrophic cardiomyopathy. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 19926015, 21964171, 27231019, 23396983). ClinVar contains an entry for this variant (Variation ID: 161381). 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. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000182707 SCV000272387 uncertain significance not specified 2018-11-16 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Computational tools suggest impact to protein. MAF 0.07%. Frequ ency too high for gene/disease (RYR2/CPVT).

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