Submissions for variant NM_001035.3(RYR2):c.1258C>T (p.Arg420Trp)

gnomAD frequency: 0.00001  dbSNP: rs190140598

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182680	SCV000235059	pathogenic	not provided	2021-12-14	criteria provided, single submitter	clinical testing	Reported in association with CPVT and/or sudden unexplained death in patients referred to GeneDx and in the published literature (Bauce et al., 2002; Nishio et al., 2006; Medeiros-Domingo et al., 2009; Anderson et al., 2016; Kawata et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on 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); Published functional studies in HEK293 cells and mouse models demonstrate a damaging effect on RYR2 receptor function (Tang et al., 2012; Okudaira et al., 2014); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 201214; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25372681, 24025405, 22221940, 15544015, 23871484, 21616285, 31231889, 22373669, 25193700, 17062961, 12934820, 26332594, 22383456, 19926015, 12106942, 22787013, 26082524, 27114410, 27452199, 27538377, 28713282, 25087098, 26153920, 28422759, 28449774, 30170228, 29925740, 29434162, 29759671, 31112425, 30898243, 30909845, 31402444, 22374134, 30847666, 26582918)
Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute	RCV000202619	SCV000257560	pathogenic	Ventricular fibrillation	2015-12-15	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219729	SCV000271448	pathogenic	Catecholaminergic polymorphic ventricular tachycardia	2015-06-25	criteria provided, single submitter	clinical testing	The p.Arg420Trp in RYR2 has been identified in 6 individuals (1 child, 2 adolesc ents, 3 adults) with a clinical diagnosis of CPVT or sudden unexplained death (B auce 2002, Tester 2004, Nishio 2006, van der Werf 2012) and segregated with dise ase in at least 6 affected relatives from two families (Bauce 2002, van der Werf 2011). The p.Arg420Trp variant has been identified in 1/8604 East Asian chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs190140598). Please note that for diseases with clinical variability or r educed penetrance, pathogenic variants may be present at a low frequency in the general population. A pathogenic role is also supported by studies of mice carry ing the variant (Okudaira 2014). In summary, this variant meets our criteria to be classified as pathogenic for CPVT in an autosomal dominant manner (http://www .partners.org/personalizedmedicine/LMM) based upon segregation studies and funct ional evidence.
Fulgent Genetics, Fulgent Genetics	RCV000515377	SCV000611314	pathogenic	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1	2017-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002470799	SCV000815379	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 420 of the RYR2 protein (p.Arg420Trp). This variant is present in population databases (rs190140598, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant RYR2-related conditions (PMID: 21616285, 22221940, 22373669, 22787013). ClinVar contains an entry for this variant (Variation ID: 201214). 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 95%. Experimental studies have shown that this missense change affects RYR2 function (PMID: 22374134, 25193700). 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: 25440180, 26153920, 28422759, 28449774). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194068	SCV001363324	pathogenic	Cardiomyopathy	2019-11-19	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.1258C>T (p.Arg420Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249018 control chromosomes (gnomAD). c.1258C>T has been reported in the literature in multiple individuals and families affected with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) or Sudden Cardiac Death (e.g. Bauce_2002, Tester_2004, Adler_2016, van der Werf_2012, Nannenberg_2012), and was shown to segregate with the disease in several families, although with a reduced penetrance (Bauce_2002, van der Werf_2012, Nannenberg_2012). These data indicate that the variant is very likely to be associated with disease. This variant was also found in one patient in cardiomyopathy panel testing in our laboratory. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in higher levels of fractional calcium release by RYR2 channels (Tang_2012). In addition, a knock-in mouse model of the R420W variant showed susceptibility to arrhythmias in response to heart stimulants (Okudaira_2014). Another missense variant affecting the same amino acid (R420Q) has been also reported in patients (HGMD), indicating the functional importance of this residue. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001194068	SCV002042891	uncertain significance	Cardiomyopathy	2021-04-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426877	SCV002681193	pathogenic	Cardiovascular phenotype	2023-12-01	criteria provided, single submitter	clinical testing	The p.R420W pathogenic mutation (also known as c.1258C>T), located in coding exon 14 of the RYR2 gene, results from a C to T substitution at nucleotide position 1258. The arginine at codon 420 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been identified in numerous individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) and/or sudden unexpected death (Tester DJ et al. Mayo Clin. Proc. 2004;79:1380-4; Nishio H et al. Circ. J. 2006;70:1402-6; Medeiros-Domingo A et al. J. Am. Coll. Cardiol. 2009;54:2065-74; van der Werf C et al. Circ Arrhythm Electrophysiol. 2012;5:748-56; Kawata H et al. Circ. J., 2016 Aug;80:1907-15). This variant has also been reported to segregate with disease (Bauce B et al. J. Am. Coll. Cardiol. 2002;40:341-9; Nannenberg EA et al. Circ Cardiovasc Genet. 2012;5:183-9). Functional studies performed in mammalian cell lines suggest this alteration has an impact on calcium signaling, and mice with this variant have a significantly higher occurrence of arrhythmias in response to heart stimulants than wild-type mice (Tang Y et al. Circ. Res. 2012;110:968-77; Okudaira N et al. Biochem. Biophys. Res. Commun. 2014;452:665-8). In addition, a pathogenic mutation (p.R420Q) has been described in the same codon (Medeiros-Domingo A et al. J Am Coll Cardiol. 2009; 54(22):2065-74). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470799	SCV002767465	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) (PMID: 12459180, PMID: 27646203, PMID: 29477366). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in one of the well established missense variant hotspots found in this protein (Decipher, PMID: 19926015, PMID: 25193700). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.Arg420Gln) has been reported multiple times as pathogenic, and has been observed in individuals with catecholaminergic polymorphic with ventricular tachycardia (CPVT) (ClinVar, PMID: 19926015). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described multiple times as pathogenic, and has been observed in many families with CPVT, commonly with incomplete penetrance (ClinVar, VCGS, PMID: 28158428). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Knock-in mice have been demonstrated to have impaired depolarization-induced calcium oscillation in cardiomyocytes, prolonged decay time and abnormal calcium ion release (PMID: 25193700). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Molecular Genetics, Royal Melbourne Hospital	RCV000219729	SCV004812478	pathogenic	Catecholaminergic polymorphic ventricular tachycardia	2023-05-04	criteria provided, single submitter	clinical testing	This sequence change in RYR2 is predicted to replace arginine with tryptophan at codon 420, p.(Arg420Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in a cytoplasmic helical region in the N-terminal domain. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (1/17,960 alleles) in the East Asian population, which is consistent with RYR2-related disease. The variant has been identified in multiple individuals with sudden unexplained cardiac death or a clinical diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT), and segregates with disease in multiple families (PMID: 12106942, 15544015, 17062961, 21616285, 22373669, 26743238). A knock-in mouse model for the variant exhibits arrhythmogenesis with abnormal calcium dynamics in cardiomyocytes (PMID: 25193700). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.88). Another missense variant c.1259G>A, p.(Arg420Gln) in the same codon with a smaller physicochemical difference has been classified as pathogenic for CPVT (ClinVar ID: 201215). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS3_Moderate, PM5, PS4_Supporting, PM2_Supporting, PP3.