Submissions for variant NM_001035.3(RYR2):c.1259G>A (p.Arg420Gln)

dbSNP: rs794728721

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182681	SCV000235060	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	Reported in association with CPVT and/or sudden unexplained death in the published literature (Medeiros-Domingo et al., 2009; van der Werf et al., 2011; Ohno et al., 2015; Shigemizu et al. 2015); Published functional studies demonstrate a damaging effect (altered the orientations of RYR2 channel domain which is required for protein stability) (Kimlicka et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24025405, 25372681, 26114861, 21616285, 22334434, 25440180, 26153920, 26132555, 27452199, 27761165, 27916777, 28422759, 28449774, 28012210, 29434162, 31112425, 31337358, 31535183, 32605058, 34135346, 34076677, 19926015, 23871484)
Ambry Genetics	RCV000617576	SCV000737475	pathogenic	Cardiovascular phenotype	2019-01-09	criteria provided, single submitter	clinical testing	The p.R420Q pathogenic mutation (also known as c.1259G>A), located in coding exon 14 of the RYR2 gene, results from a G to A substitution at nucleotide position 1259. The arginine at codon 420 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been seen in several cohorts of patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), suspected long QT syndrome, or sudden death (Medeiros-Domingo A et al. J Am Coll Cardiol. 2009; 54(22):2065-74; van der Werf C et al. J Am Coll Cardiol. 2011; 57(22):2244-54; Lahrouchi N et al. J Am Coll Cardiol. 2017;69(17):2134-2145). This alteration also segregated with disease in a large family with CPVT (Domingo D et al. Rev Esp Cardiol (Engl Ed). 2015; 68(5):398-407). In addition, functional in vitro studies suggest this alteration causes conformational changes that likely activate the channel (Kimlicka L et al. Structure. 2013; 21(8):1440-9), while additional assays, utilizing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) or knock-in (KI) mouse models, showed that this alteration disrupts protein function, resulting in increased diastolic Ca2+ release (Novak A et al. J Cell Mol Med. 2015;19:2006-18; Wang YY et al. JCI Insight. 2017;2(8). Epub ahead of print. doi:10.1172/jci.insight.91872). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV002288789	SCV001405644	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 420 of the RYR2 protein (p.Arg420Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 19926015, 23595086, 25440180, 26132555, 28449774). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201215). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RYR2 function (PMID: 26153920, 28422759). This variant disrupts the p.Arg420 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21616285, 22221940, 22373669, 22787013). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000182681	SCV001449861	pathogenic	not provided	2016-06-13	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288789	SCV002581482	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2022-02-25	criteria provided, single submitter	clinical testing
Medical Research Institute, Tokyo Medical and Dental University	RCV000190228	SCV000222079	uncertain significance	Long QT syndrome		no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000182681	SCV000280442	likely pathogenic	not provided	2015-03-19	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg420Gln (R420Q; c.1259 G>A) in the RYR2 gene This variant has been previously reported in at least 5 unrelated individuals with CPVT. There is no published segregation data. Medeiros-Domingo et al. (2009) reported Arg420Gln in two unrelated individuals from a group diagnosed with either CPVT or gene-negative exercise-induced LQTS (QTc < 480 msec). van der Werf et al. (2011) observed it in one individual with CPVT. GeneDx reports finding it in two other unrelated individuals tested for CPVT. Variation at this amino acid and at other nearby residues has been associated with CPVT, suggesting the functional importance of this codon and this protein region: Arg420Trp, Thr415Arg, Ile419Phe (HGMD via GeneDx). Amino acid 420 falls in the N-terminal domain of RYR2, where other disease-causing mutations have been shown to cluster. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged arginine with a polar glutamine. The arginine at this location is highly conserved across 42/43 mammalian species sequenced. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.994. In total the variant has not been seen in ~7200 individuals from published controls and publicly available population datasets. Not many of these controls are ancestry-matched with our patient, however. (Our patient has Mexican and Spanish ancestry.) There is no variation at this codon in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4100 Caucasian and ~1900 African American individuals (as of May 28, 2013). No non-clinical variation at this residue is found in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). No variation at this codon is present in 1000 Genomes, which contains 66 individuals of Mexican ancestry from Los Angeles, as of January 8, 2013. (Out of 1092 genotypes in phase 1, there are 66 people of Mexican ancestry from LA, 55 Puerto Ricans, 60 Colombians from Medellin, totaling 181 Hispanic or Latino individuals.) The variant was not observed in published controls: Medeiros-Domingo et al. (2009) did not find the variant in 200 controls (100 Caucasian and 100 Black). van der Werf et al. (2011) and GeneDx did not report additional controls.