Submissions for variant NM_001035.3(RYR2):c.7202G>A (p.Arg2401His)

dbSNP: rs794728756

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182760	SCV000235145	pathogenic	not provided	2019-06-04	criteria provided, single submitter	clinical testing	Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 201279; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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); A different missense change at this residue (R2401L) has been reported in the published literature in association with CPVT (Creighton et al., 2006); This variant is associated with the following publications: (PMID: 24136861, 15749201, 24025405, 19926015, 21964171, 20646679, 21616285, 25713214, 29453246, 25844899, 28449774, 30403697, 28152038, 20851825, 28100344, 31337358)
Blueprint Genetics	RCV000208074	SCV000264186	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2015-10-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000247473	SCV000318695	likely pathogenic	Cardiovascular phenotype	2017-06-27	criteria provided, single submitter	clinical testing	The p.R2401H variant (also known as c.7202G>A), located in coding exon 47 of the RYR2 gene, results from a G to A substitution at nucleotide position 7202. The arginine at codon 2401 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in patients with known or suspected catecholaminergic polymorphic ventricular tachycardia (CPVT) (Aizawa Y et al. Int J Cardiol. 2005;99(2):343-345; Liu J et al. Acta Cardiol Sin. 2011;27:115-119; van der Werf C et al. J Am Coll Cardiol. 2011;57:2244-54; Roston TM et al. Circ Arrhythm Electrophysiol. 2015;8:633-42). In one case, this alteration was detected in a proband with CPVT whose asymptomatic mother was reportedly mosaic (Roux-Buisson N et al. Europace. 2011;13:130-2). This alteration was reported as occuring de novo in an 8-year-old drowning victim, and in a patient with reported CPVT (Tester DJ et al. Mayo Clin Proc. 2011;86:941-7; Liu X et al. Zhonghua Xin Xue Guan Bing Za Zhi. 2017;45:39-43). Another alteration affecting this amino acid (p.R2401L) was detected in a 12-year-old boy with sudden death (Creighton W et al. J Mol Diagn. 2006;8:62-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000208074	SCV002235118	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2021-06-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 15749201, 20851825, 28100344). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 201279). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 2401 of the RYR2 protein (p.Arg2401His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000208074	SCV002320697	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2021-05-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000182760	SCV002544384	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	RYR2: PM1, PM2, PM5, PS4:Moderate, PP3, PP4