rs794728756

Positions:

• chr1-237640983-G-A
• chr1-237640983-G-C
• chr1-237640983-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001035.3(RYR2):​c.7202G>A​(p.Arg2401His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2401C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.93

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

RYR2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237640983-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 1-237640983-G-A is Pathogenic according to our data. Variant chr1-237640983-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237640983-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.7202G>A	p.Arg2401His	missense_variant	47/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.7202G>A	p.Arg2401His	missense_variant	47/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.7202G>A		non_coding_transcript_exon_variant	47/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.7202G>A	p.Arg2401His	missense_variant	47/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.7202G>A	p.Arg2401His	missense_variant	47/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 16, 2021	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	May 17, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2019	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	RYR2: PM1, PM2, PM5, PS4:Moderate, PP3, PP4 -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.92		Gain of catalytic residue at R2401 (P = 0.0965);.;
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.55
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794728756; hg19: chr1-237804283; COSMIC: COSV63663412;