rs794728811

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001035.3(RYR2):c.14876G>A(p.Arg4959Gln) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4959W) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.60

Publications

18 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 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, 6 uncertain in NM_001035.3

PM2

Very rare variant in population databases, with high coverage;

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, 0.914

PP5

Variant 1-237832619-G-A is Pathogenic according to our data. Variant chr1-237832619-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 201365.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.14876G>A	p.Arg4959Gln	missense_variant	Exon 105 of 105	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 link	c.14876G>A	p.Arg4959Gln	missense_variant	Exon 105 of 105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.14894G>A	p.Arg4965Gln	missense_variant	Exon 106 of 106			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.*5968G>A		non_coding_transcript_exon_variant	Exon 104 of 104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000609119.2 link	n.*5968G>A		3_prime_UTR_variant	Exon 104 of 104	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 18, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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: 16188589, 29766881, 24025405, 19926015, 20354512, 15765137, 15721128, 25713214, 29453246, 25514987, 31112425, 28135719, 31785789, 31737537, 14571276, 27231019, 33825858, 35101670, 34725342, 35135837) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR2: PP1:Strong, PM1, PM2, PM6, PS4:Moderate, PP3 -

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Pathogenic:5

Jun 25, 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 4959 of the RYR2 protein (p.Arg4959Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with catecholaminergic polymorphic ventricular tachycardia, and RYR2-related disease (PMID: 14571276, 15721128, 16188589, 29453246). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201365). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Feb 01, 2022

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Likely Pathogenic, for Ventricular tachycardia, catecholaminergic polymorphic, 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:14571276,16188589,27231019,15721128). PP1-Moderate => PP1 upgraded in strength to Moderate (PMID:15721128). -

Jun 28, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP1-S,PM2,PP3. -

Jul 27, 2016

Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The patient was diagnosed with typical polymorphic ventricular tachycardia at the age of 12 followed by ICD implantation. No relatives are available for genetic testing. -

Cardiovascular phenotype

Pathogenic:1

Jun 24, 2019

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R4959Q variant (also known as c.14876G>A), located in coding exon 105 of the RYR2 gene, results from a G to A substitution at nucleotide position 14876. The arginine at codon 4959 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in several individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT), Long QT syndrome (LQTS), and developmental delay (Laitinen PJ et al. Eur. J. Hum. Genet., 2003 Nov;11:888-91; Jabbari J et al. Circ Cardiovasc Genet, 2013 Oct;6:481-9; Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74; Tester DJ et al. Heart Rhythm, 2005 Oct;2:1099-105; Nature, 2017 02;542:433-438; Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424; Avari Silva JN et al. J Am Heart Assoc, 2016 05;5:). 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

0.73

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;T

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

L;.

PhyloP100

9.6

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.0

D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

D;.

Polyphen

1.0

D;.

Vest4

0.85

MutPred

0.70

Loss of ubiquitination at K4960 (P = 0.1172);.;

MVP

0.99

MPC

1.6

ClinPred

0.99

GERP RS

5.2

Varity_R

0.57

gMVP

0.82

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Other links and lift over