chr1-237377386-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 10.0

Publications

114 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 2
Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
catecholaminergic polymorphic ventricular tachycardia 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RYR2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 7 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 VariationId is 201195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.

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 VariationId is 201194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.527G>A	p.Arg176Gln	missense_variant	Exon 8 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RYR2	ENST00000366574.7 link	c.527G>A	p.Arg176Gln	missense_variant	Exon 8 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2 link	c.527G>A	p.Arg176Gln	missense_variant	Exon 8 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2 link	n.527G>A		non_coding_transcript_exon_variant	Exon 8 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1

Pathogenic:3

May 04, 2015

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 11159936, 16188589, 18752142, 20106799; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 201194). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR2 function (PMID: 16873551, 20157052, 27482086). For these reasons, this variant has been classified as Pathogenic.

Jan 01, 2016

Center for Medical Genetics Ghent, University of Ghent

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:2

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 22, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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)

RYR2-related disorder

Pathogenic:1

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS2, PS3, PS4, PM1, PM2, PP3

Arrhythmogenic right ventricular dysplasia 2

Pathogenic:1

Jan 11, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Cardiovascular phenotype

Pathogenic:1

Mar 17, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. 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

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.0

D;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.80

ClinPred

1.0

GERP RS

5.2

Varity_R

0.85

gMVP

0.77

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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