ClinVar Miner

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

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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).
Invitae RCV001084483 SCV000285719 likely benign Catecholaminergic polymorphic ventricular tachycardia 2019-12-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589142 SCV000343218 uncertain significance not provided 2016-07-14 criteria provided, single submitter clinical testing
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.
Ambry Genetics RCV000619628 SCV000735621 likely benign Cardiovascular phenotype 2019-05-03 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;Other data supporting benign classification
Color RCV000771801 SCV000904498 likely benign Cardiomyopathy 2019-11-18 criteria provided, single submitter clinical testing
Mendelics RCV000148833 SCV001135598 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589142 SCV001147754 uncertain significance not provided 2016-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001102502 SCV001259175 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2019-01-18 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.
Illumina Clinical Services Laboratory,Illumina RCV000148833 SCV001259176 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2019-01-18 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000771801 SCV001333885 uncertain significance Cardiomyopathy 2017-12-05 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148833 SCV000190574 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2014-06-01 no assertion criteria provided research

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