Submission Details

The ryanodine receptor 2 (RYR2) calcium channel has been linked in the literature to autosomal dominant, catecholaminergic polymorphic ventricular tachycardia (CPVT), calcium release deficiency syndrome (CRDS), and hypertrabeculation. Variants in RYR2 were first associated with CPVT in 2001 (Priori et al, 2001; PMID 11208676), hypertrabeculation (reported as left ventricular non-compaction) in 2009 (Marjamaa et al, 2009; PMID 19216760), and CRDS in 2021 (Sun et al, 2021; PMID 33536282). RYR2 variants associated with CPVT have been shown to increase the sensitivity of the calcium channel to caffeine (George et al, 2003; PMID 12919952) where CRDS associated variants decrease the sensitivity of the channel to caffeine (Zhong et al, 2021; PMID 33825858, Roston et al, 2022; PMID 34730774). Hypertrabeculation has been identified primarily in probands presenting clinically with CPVT carrying RYR2 exon 3 deletions and at least one missense variant presenting with what the authors assert as atypical CPVT (Marjamaa et al, 2009; PMID 19216760, Ohno et al, 2014; PMID 24394973, Roston et al, 2017; PMID 27646203). This curation will only consider cases presenting with CPVT. A curation for CRDS will be conducted in the future once clinical phenotypes can be shown to consistently differentiate probands with CPVT and CRDS.

RYR2 variants are not the only genetic cause for CPVT but do represent the majority (nearly half) of reports associated with monogenic CPVT. Most disease-causing variants in RYR2 are missense variants which tend to cluster in several pathogenic hotspots. Human genetic evidence supporting this gene-disease relationship includes case-level data, segregation data, and case-control data. A significant excess of rare (MAF<0.0001) RYR2 variants was observed in CPVT cohorts compared to ExAC population controls (Kapplinger et al, 2018; PMID 29453246), with rare variant yields higher in definitive CPVT cases (59%) than possible CPVT cases (31%) and all CPVT genetic testing referrals (18%). There is a plethora of case-level data to support the association of RYR2 with CPVT, including numerous examples of de novo inheritance (Priori et al, 2001; PMID 11208676, Priori et al, 2002; PMID 12093772). Segregation of RYR2 variants with disease in family pedigrees has also been noted, in particular a 1404 member extended pedigree from Gran Canaria island in Spain, covering 10 generations with 178 carriers of the RYR2 p.Gly357Ser variant (Wangüemert et al, 2015; PMID 25814417). In addition, this gene-disease assertion is supported by experimental evidence, including functional alteration, non-human model organism, and rescue in non-human model organism. Variants detected in patients have been introduced to non-patient cells in numerous studies (including HEK293, HL-1 cardiomyocytes and mouse ventricular cells) with clear effects on Ca2+ sensitivity and release (Wangüemert et al, 2015; PMID 25814417; George et al, 2003; PMID 12919952, Loaiza et al, 2013; PMID 23152493, Zhao et al, 2014; PMID 25775566). Knock-in mice have been generated for several RYR2 variants detected in CPVT patients which demonstrate arrhythmia phenotypes typical of CPVT (Cerrone et al, 2005; PMID 15890976, Kannankeril et al, 2006; PMID 16873551, Loaiza et al, 2013; PMID 23152493). Rescue of the CPVT phenotype in mouse models has also been noted, with correction of the p.Arg176Gln variant by AAV-CRISPR leading to a significant reduction in arrhythmias compared to uncorrected knock in mice (Pan et al, 2018; PMID 30355031). Additional evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. In summary, RYR2 variants are definitively associated with autosomal dominant CPVT. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time leading to a Definitive classification. Note: All CPVT genes were curated by 3 separate blinded teams. This gene-disease pair was originally evaluated by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP 7). The evidence summary was updated 22nd November, 2024 by the ClinGen Hereditary Cardiovascular Disease GCEP. This update was to address gene-disease assertions that have been made since the original curation, and neither the curated disease entity nor classification were changed.

RYR2 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). RYR2 was the first gene to be associated with CPVT in 2001. It is the predominant gene associated with the condition, with approximately half of all CPVT probands carrying a pathogenic RYR2 variant. Most disease-causing variants in RYR2 are missense variants which tend to cluster in several pathogenic hotspots. Human genetic evidence supporting this gene-disease relationship includes case-level data, segregation data, and case-control data. A significant excess of rare (MAF<0.0001) RYR2 variants was observed in CPVT cohorts compared to ExAC population controls (Kapplinger et al, 2018, PMID:29453246), with rare variant yields higher in definitive CPVT cases (59%) than possible CPVT cases (31%) and all CPVT genetic testing referrals (18%). There is a plethora of case-level data to support the association of RYR2 with CPVT, including numerous examples of de novo inheritance (Priori et al, 2001, PMID:11208676; Priori et al, 2002, PMID:12093772). Segregation of RYR2 variants with disease in family pedigrees has also been noted, in particular a 1404 member extended pedigree from Gran Canaria island in Spain, covering 10 generations with 178 carriers of the RYR2:p.Gly357Ser variant (Wangüemert et al, 2015, PMID:25814417). In addition, this gene-disease assertion is supported by experimental evidence, including functional alteration, non-human model organism, and rescue in non-human model organism. Variants detected in patients have been introduced to non-patient cells in numerous studies (including HEK293, HL-1 cardiomyocytes and mouse ventricular cells) with clear effects on Ca2+ sensitivity and release (Wangüemert et al, 2015, PMID:25814417; George et al, 2003, PMID:12919952; Loaiza et al, 2013, PMID:23152493; Zhao et al, 2014, PMID:25775566). Knock-in mice have been generated for several RYR2 variants detected in CPVT patients which demonstrate arrhythmia phenotypes typical of CPVT (Cerrone et al, 2005, PMID:15890976; Kannankeril et al, 2006, PMID:16873551; Loaiza et al, 2013, PMID:23152493). Rescue of the CPVT phenotype in mouse models has also been noted, with correction of the p.Arg176Gln variant by AAV-CRISPR leading to a significant reduction in arrhythmias compared to uncorrected knock in mice (Pan et al, 2018, PMID:30355031). Additional evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. In summary, RYR2 variants are definitively associated with autosomal dominant CPVT. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).