rs794728708

Positions:

• chr1-237377386-G-A
• chr1-237377386-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.527G>A​(p.Arg176Gln) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-237377386-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201195.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, 0.976
• PP5: Variant 1-237377386-G-A is Pathogenic according to our data. Variant chr1-237377386-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 201194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237377386-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.527G>A	p.Arg176Gln	missense_variant	8/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.527G>A	p.Arg176Gln	missense_variant	8/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.527G>A		non_coding_transcript_exon_variant	8/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.527G>A	p.Arg176Gln	missense_variant	8/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.527G>A	p.Arg176Gln	missense_variant	8/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Jan 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 11, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 16873551, 20157052, 27482086). 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. ClinVar contains an entry for this variant (Variation ID: 201194). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 11159936, 16188589, 18752142, 20106799; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 176 of the RYR2 protein (p.Arg176Gln). -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 04, 2015	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2020	Reported in association with LQTS and CPVT, also described as "ARVD2" in some publications (Tiso et al., 2001; Bauce et al., 2002; Tester et al., 2005; Berge et al., 2008; Haugaa et al., 2010); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 201194; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as mice that are heterozygous for this variant developed frequent PVCs with isoproterenol while the wild-type mice did not and concluded that R176Q is sufficient to cause catecholamine-induced VT (Kannankeril et al., 2006; Mathur et al., 2009); Additional published functional studies demonstrate a damaging effect in HEK293 cells as this variant results an increase in peak calcium release (Thomas et al., 2004; Jiang et al., 2005; Tang et al., 2012); 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); This variant is associated with the following publications: (PMID: 19603549, 24136861, 22158709, 23978697, 23152493, 11159936, 31112425, 19226252, 24025405, 16239587, 15364613, 25372681, 16873551, 16188589, 20106799, 22374134, 20009080, 12106942, 18752142, 19926015, 25901278) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -

Arrhythmogenic right ventricular dysplasia 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 11, 2020

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2019

The p.R176Q pathogenic mutation (also known as c.527G>A), located in coding exon 8 of the RYR2 gene, results from a G to A substitution at nucleotide position 527. The arginine at codon 176 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in association with arrhythmia phenotypes, including detection in individuals with syncope with and without reported QTc prolongation, and catecholaminergic polymorphic ventricular tachycardia (CPVT) (Tester DJ et al. Heart Rhythm, 2005 Oct;2:1099-105; Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74; Berge KE et al. Scand. J. Clin. Lab. Invest., 2008;68:362-8; Haugaa KH et al. Europace, 2010 Mar;12:417-23). This alteration has also been reported to co-occur with a second RYR2 variant in a family with arrhythmogenic right ventricular cardiomyopathy (Tiso N et al. Hum. Mol. Genet., 2001 Feb;10:189-94). In addition, inducible ventricular arrhythmias including bi-directional and polymorphic ventricular tachycardia have been demonstrated in mouse models expressing p.R176Q (Kannankeril PJ et al. Proc. Natl. Acad. Sci. U.S.A., 2006 Aug;103:12179-84; Li N. Int. J. Cardiol. 2017 Jan;227:668-673). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.84		Loss of sheet (P = 0.1501);.;
MVP		0.97
MPC		0.53
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.85
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs794728708; hg19: chr1-237540686; COSMIC: COSV63694898;