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

gnomAD frequency: 0.00063  dbSNP: rs149514924

Total submissions: 15

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, Mass General Brigham 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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148833	SCV000285719	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000771801	SCV000904498	likely benign	Cardiomyopathy	2019-11-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000148833	SCV001135598	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589142	SCV001147754	uncertain significance	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001102502	SCV001259175	uncertain significance	Arrhythmogenic right ventricular dysplasia 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 Laboratory Services, Illumina	RCV000148833	SCV001259176	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 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	RCV000589142	SCV001474130	uncertain significance	not 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 1	2014-06-01	no assertion criteria provided	research