ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.649A>G (p.Ile217Val) (rs200642525)

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Total submissions: 9
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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,Partners HealthCare 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,; 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000171760 SCV000233007 uncertain significance not provided 2016-12-21 criteria provided, single submitter clinical testing
GeneDx RCV000171760 SCV000235040 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing The I217V variant in the RYR2 gene has been reported in one family in association with sudden unexplained death (SUD) (Tester D et al., 2012). This study did not observe I217V in at least 400 controls and it was also not observed with any significant frequency in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Additionally, this substitution occurs at a position that is conserved across species and I217V is located in the N-terminal mutation hot spot" domain in the RYR2 gene (Medeiros-Domingo A et al., 2009). However, the I217V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function."
Invitae RCV000229055 SCV000285740 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 217 of the RYR2 protein (p.Ile217Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs200642525, ExAC 0.03%). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy, in one individual affected with hypertrophic cardiomyopathy that suffered a sudden unexplained death and in one family with a sudden unexplained death. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 22677073, 27194543, 27930701). ClinVar contains an entry for this variant (Variation ID: 165072). 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"). 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.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000415633 SCV000493800 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2016-01-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619874 SCV000736171 uncertain significance Cardiovascular phenotype 2017-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
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
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;, 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.

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