rs794728811

Positions:

• chr1-237832619-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.60

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 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, 5 uncertain in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.914
• PP5: Variant 1-237832619-G-A is Pathogenic according to our data. Variant chr1-237832619-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237832619-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.14876G>A	p.Arg4959Gln	missense_variant	105/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.14876G>A	p.Arg4959Gln	missense_variant	105/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*5968G>A		non_coding_transcript_exon_variant	104/104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*5968G>A		3_prime_UTR_variant	104/104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RYR2: PP1:Strong, PM1, PM2, PM6, PS4:Moderate, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 15, 2023	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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jun 28, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP1-S,PM2,PP3. -
Pathogenic, criteria provided, single submitter	research	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	Jul 27, 2016	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2019

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	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.
PrimateAI	Pathogenic	0.80	T
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	D
GERP RS		5.2
Varity_R		0.57
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs794728811; hg19: chr1-237995919; COSMIC: COSV63658473;