ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1259G>A (p.Arg420Gln) (rs794728721)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182681 SCV000235060 pathogenic not provided 2018-04-04 criteria provided, single submitter clinical testing The R420Q pathogenic variant in the RYR2 gene was first reported in two unrelated individuals from a cohort of patients clinically diagnosed with either CPVT or possible long QT syndrome (Medeiros-Domingo et al., 2009). It has subsequently been identified in a 15-year-old female with CPVT who experienced syncope at 14 years of age (van der Werf et al., 2011), a 7-year-old female with cardiac arrest who inherited R420Q from her mother with a history of syncope (Ohno et al., 2015), and a 12-year-old individual with syncope during swimming who later experienced sudden death at 17 years of age (Shigemizu et al. 2015). Additionally, this variant has been identified in nine relatives with a clinical diagnosis of CPVT from a large Spanish family who also had a history of sinus bradycardia, atrial and junctional arrhythmias and/or giant post-effort U-waves (Domingo et al., 2015). The R420Q variant results in a semi-conservative amino acid substitution. Functional characterization of the R420Q demonstrated that this variant altered the orientations of RYR2 channel domain thus ablating chloride binding which is required for protein stability (Kimlicka et al., 2013). Additional functional studies by Domingo et al. (2015) suggest that R420Q causes abnormal RYR2 channel function through either a gain- or loss-of-function effect, depending on the concentration of cystolic intracellular calcium. Furthermore, a pathogenic variant at the same residue (R420W) has been reported in HGMD in association with polymorphic ventricular tachycardia (Stenson et al., 2014), further supporting the functional importance of this residue. Furthermore, the R420Q variant is not observed in large population cohorts (Lek et al., 2016).
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 RCV001233065 SCV001405644 pathogenic Catecholaminergic polymorphic ventricular tachycardia 2020-02-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 420 of the RYR2 protein (p.Arg420Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of catecholaminergic polymorphic ventricular tachycardia (CPVT) and observed to segregate with CPVT in a family (PMID: 25440180, 23595086, 26132555, 19926015, 28449774). ClinVar contains an entry for this variant (Variation ID: 201215). This variant has been reported to affect RYR2 protein function (PMID: 28422759, 26153920). 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: 22787013, 22221940, 22373669, 21616285). 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 Karolinska University Hospital,Karolinska University Hospital RCV000182681 SCV001449861 pathogenic not provided 2016-06-13 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.

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