ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1258C>T (p.Arg420Trp) (rs190140598)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182680 SCV000235059 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing The R420W pathogenic variant in the RYR2 gene has been published multiple times in association with CPVT and/or sudden unexplained death (Bauce et al., 2002; Nishio et al., 2006; Medeiros-Domingo et al., 2009; Anderson et al., 2016; Kawata et al., 2016). This variant has also segregated with disease in several affected relatives from multiple families, as reported by Bauce et al. (2002) and Nannenberg et al. (2012), and observed at GeneDx. Additionally, the R420W variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016). The R420W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the R420W variant is 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). Another pathogenic missense variant in the same residue (R420Q) has been reported in the Human Gene Mutation Database in association with RYR2-related disorders (Medeiros-Domingo et al., 2009), further supporting the functional importance of this residue. Finally, functional studies in HEK293 cells and mouse models suggest that R420W impairs RYR2 receptor function (Tang et al., 2012; Okudaira et al., 2014).
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, Partners HealthCare 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, familial, 2; Catecholaminergic polymorphic ventricular tachycardia type 1 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000219729 SCV000815379 pathogenic Catecholaminergic polymorphic ventricular tachycardia 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 420 of the RYR2 protein (p.Arg420Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs190140598, ExAC 0.01%). This variant has been reported in several individuals affected with RYR2-related conditions (PMID: 22787013, 22221940, 22373669, 21616285). ClinVar contains an entry for this variant (Variation ID: 201214). Experimental studies have shown that this missense change reduces the threshold for calcium release termination and increases the fractional release in vitro (PMID: 22374134). Additionally, knock-in mice cardiomyocytes show an arrythmogenic phenotype (PMID: 25193700). A different missense substitution at this codon (p.Arg420Gln) has been determined to be pathogenic (PMID: 25440180, 26153920, 28449774, 28422759). This suggests that the arginine residue is critical for RYR2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.

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