ClinVar Miner

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

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589142 SCV000235087 likely benign not provided 2020-09-30 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26332594, 23396983, 24055113, 24025405, 25637381, 25608792, 23204524, 25351510, 21964171, 19926015, 27538377, 27231019, 27153395, 28404607, 28492532, 25163546, 26899768, 31112425, 30847666)
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 2020-11-20 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Other data supporting benign classification;Subpopulation frequency in support of benign classification
Color Health, Inc 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
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256779 SCV001433223 uncertain significance Conduction disorder of the heart 2020-01-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287438 SCV001474130 uncertain significance none provided 2020-03-20 criteria provided, single submitter clinical testing The RYR2 c.3038G>A; p.Arg1013Gln variant (rs149514924) is reported in the literature in ___ individuals affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Medeiros-Domingo 2009), arrhythmogenic right ventricular cardiomyopathy (Avari 2016), or hypertrophic cardiomyopathy (Lopes 2013), although none of the reports provide a clear association with disease. This variant is reported in ClinVar (Variation ID: 161381), and is found in the general population with an overall allele frequency of 0.048% (135/280564 alleles) in the Genome Aggregation Database. Recent studies suggest the prevalence of the variant is higher than expected for pathogenic variants in RYR2 (Giudicessi 2019, Paludan-Muller 2017). The arginine at codon 1013 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. While the high population frequency suggests that this variant may be a benign polymorphism, given the lack of clear clinical and functional data, the significance of the p.Arg1013Gln variant is uncertain at this time References: Avari Silva JN et al. Implantable Loop Recorder Monitoring for Refining Management of Children With Inherited Arrhythmia Syndromes. J Am Heart Assoc. 2016 May 26;5(6). pii: e003632. Giudicessi JR et al. Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. Circ Genom Precis Med. 2019 May;12(5):e002510. Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. Medeiros-Domingo A et al. The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis. J Am Coll Cardiol. 2009 Nov 24;54(22):2065-74. Paludan-Muller C et al. Integration of 60,000 exomes and ACMG guidelines question the role of Catecholaminergic Polymorphic Ventricular Tachycardia-associated variants. Clin Genet. 2017 Jan;91(1):63-72.
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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