Submissions for variant NM_001035.3(RYR2):c.649A>G (p.Ile217Val)

gnomAD frequency: 0.00029  dbSNP: rs200642525

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171760	SCV000055281	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151754	SCV000200134	uncertain significance	not specified	2015-04-03	criteria provided, single submitter	clinical testing	The p.Ile217Val variant in RYR2 has been reported in 1 Caucasian individual who succumbed to SCD (Tester 2012) and was identified by our laboratory in 1 Caucasi an adult with RCM and did not segregate with disease in 1 affected relative. Thi s variant has been identified in 17/66726 of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200642525). Isoleucine (Ile) is not conserved in evolutionarily distant species and the cha nge to valine (Val) is present in Mexican tetra and lamprey. Additional computat ional prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ile217Val variant i s uncertain.
Eurofins Ntd Llc (ga)	RCV000171760	SCV000233007	uncertain significance	not provided	2016-12-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000171760	SCV000235040	uncertain significance	not provided	2022-08-25	criteria provided, single submitter	clinical testing	Reported in association sudden unexplained death, hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) in the published literature; however, some probands were found to harbor additional cardiogenetic variants (Tester et al., 2012; Medeiros-Domingo et al., 2016; Sanchez et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; 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); This variant is associated with the following publications: (PMID: 25925909, 24025405, 22677073, 25372681, 27930701, 27153395, 27194543, 27538377, 28404607, 33232181, 28988457, 33825858, Olubando2020, 29511324)
Invitae	RCV001098450	SCV000285740	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619874	SCV000736171	likely benign	Cardiovascular phenotype	2019-11-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000151754	SCV000740447	uncertain significance	not specified	2017-02-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098450	SCV001254814	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2019-11-14	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000415633	SCV001254815	benign	Arrhythmogenic right ventricular dysplasia 2	2019-11-14	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171188	SCV001333880	uncertain significance	Cardiomyopathy	2017-11-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171188	SCV001356997	likely benign	Cardiomyopathy	2019-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151754	SCV001362242	likely benign	not specified	2019-07-01	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.649A>G (p.Ile217Val) results in a conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor (IPR014821) domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 249166 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.649A>G has been reported in the literature in individuals affected with a variety of cardiac phenotypes such as syncope, HCM, ARVC, and arrythmogenic cardiomyopathy (Tester_2012, Sanchez_2016, Medeiros-Domingo_2017, Mates_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least one co-occurrence with another pathogenic variant has been reported at our laboratory (MYBPC3, c.2309-2A>G, diagnostic of HCM), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Both ACMG criteria BS1 and BP5 are applicable in our ascertainment. Based on the evidence outlined above, the variant was classified as likely benign.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415633	SCV000493800	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2016-01-27	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000171760	SCV000924922	uncertain significance	not provided	2017-09-07	no assertion criteria provided	provider interpretation	p.Ile217Val (c.649A>G) in exon 9 of the RYR2 gene (NM_001035.2; ENST00000366574; chr1-237550653-A-G) SCICD Classification: variant of uncertain significance, likely benign based on high prevalence in some ethnic groups. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: Disease-causing variants in RYR2 are the cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Exon-level evidence: Disease-causing variants in RYR2 cluster within 3 hot-spot regions: the N-terminal domain (residues 77-433), the central domain (residues 2246-2534), and the C-terminal domain (residues 3778-4959) (Yano et al. 2006). This variant is located within the N-terminal domain. Deletions of exon 3 have previously been reported in association with CPVT in at least 5 unrelated families with very strong segregation data and functional data (Bhuiyan et al. 2007, Marjamaa et al. 2009, Medeiros-Domingo et al. 2009, Kawamura et al. 2013, Lobo et al. 2011, Tang et al., 2012). Region-level evidence: This variant is located in a region of RYR2 in which the amount of variation in controls is significantly higher than the amount of variation in cases (Amr et al. 2016). Case data (not including our patient): at least 11 individuals (ARVC, unexplained cardiac arrest, unselected) ClinVar: this variant has been submitted by 5 other labs with conflicting interpretations of pathogenicity LMM (VUS): seen in 2 Caucasian patients: one with sudden cardiac death and another with restricted cardiomyopathy. This variant did not segregate with disease in the RCM family. Redundant with Tester 2012. ClinSeq/NIH (likely benign) EGL (likely benign) GeneDx (likely benign) Oregon Health and Sciences University (VUS) Cases in the literature: Tester et al. 2012: 1/173 cases of SCD. Patient was a 21yo male who syncopized prior to SCD. He had a family history of SCD. He had two other variants in RYR2 that are ?classification. Redundant with LMM's case. Ng et al 2017: Present in 1/870 individuals who underwent whole exome sequencing. They were not selected for inherited cardiovascular disease. Sanchez-Molero et al. 2016: Present in 1/798 forensic cases who died suddenly and whose death remained unexplained. Landstrom et al. 2017: 1/6517 individuals who underwent whole exome sequencing at a clinical laboratory. These patients were not selected for cardiovascular disease. Medeiros-Domingo et al 2017: 1/14 unrelated individuals who underwent WES for ARVC. 70yo male with definite ARVC. Had another variant in DSG2 (pathogenicity f this variant not evaluated). Segregation data: 1 family, 2 individuals, did not segregate (LMM). Functional data: none In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align- GVGD: "Class C25")." Conservation data: The isoleucine at codon 217 is completely conserved across mammals, but not all species. Neighboring amino acids are also well conserved. Nearby pathogenic variants at this codon or neighboring codons: Per ClinVar, a variant at a nearby codon, Q2200E, is classified as likely pathogenic. Population data: Highest MAF in individuals of European descent = 0.036%. The variant was reported online in 48 of 138,532 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 45 of 63,294 individuals of Eurpean descent (MAF=0.035%), 2 of 12,007 individuals of African descent and 1 of 17,209 individuals of Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.