rs794728753

Variant names:

• chr1-237640940-G-A
• rs794728753
• NM_001035.3:c.7159G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-237640940-G-A
• chr1-237640940-G-C

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.7159G>A​(p.Ala2387Thr) variant causes a missense change. 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. A2387V) 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:5
• Conservation: PhyloP100: 6.64

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr1-237640941-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201277.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, 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, 0.953
• PP5: Variant 1-237640940-G-A is Pathogenic according to our data. Variant chr1-237640940-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237640940-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.7159G>A	p.Ala2387Thr	missense_variant	Exon 47 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.7159G>A	p.Ala2387Thr	missense_variant	Exon 47 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.7159G>A		non_coding_transcript_exon_variant	Exon 47 of 104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.7159G>A	p.Ala2387Thr	missense_variant	Exon 47 of 106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.7159G>A	p.Ala2387Thr	missense_variant	Exon 47 of 105			ENSP00000499653.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 18, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19398665, 16391617, 24025405, 24136861, 19926015, 23595086, 15131021, 22221940, 31112425, 29434162, 33825858, Olubando2020, 16188589, 17052226, 26189708, 29453246, 34076677, 30847666, 28600387, 31737537, 28237968, 32553227, 35135837, 32152366) -

Sep 13, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia Pathogenic:1

Feb 17, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala2387Thr variant in RYR2 has been reported in 4 individuals with clinica l features of CPVT (Tester 2005, Medeiros-Domingo 2009, Walsh 2014) and was iden tified by our laboratory to have probably occurred de novo in 1 adult with CPVT. It was absent from large population studies. This variant is located in the ce ntral domain of the RYR2 protein where other disease-causing variants are cluste red (Yano 2006, Walsh 2014) and another variant at this position (p.Ala2387Pro) has been identified in individuals with CPVT (Bagattin 2004, Steriotis 2012), su ggesting that a change at this position may not be tolerated. Computational pred iction tools and conservation analysis also suggest that this variant may impact the protein, though this information is not predictive enough to determine path ogenicity. In summary, although additional studies are required to fully establ ish its clinical significance, the p.Ala2387Thr variant is likely pathogenic. -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Jun 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala2387 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 15131021, 16188589, 19398665, 23595086, 28237968, 28600387), which suggests that this may be a clinically significant amino acid residue. 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: 201276). This missense change has been observed in individuals with cardiac arrest and/or catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 16188589, 19398665, 28237968, 28600387). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2387 of the RYR2 protein (p.Ala2387Thr). -

Cardiovascular phenotype Pathogenic:1

Nov 22, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A2387T variant (also known as c.7159G>A), located in coding exon 47 of the RYR2 gene, results from a G to A substitution at nucleotide position 7159. The alanine at codon 2387 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in several patients reported to have catecholaminergic polymorphic ventricular tachycardia (CPVT), and has been detected in CPVT or sudden cardiac arrest cohorts with varying levels of clinical detail (Tester DJ et al. Heart Rhythm, 2005;2:1099-105; Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009;54:2065-74; Hayashi M et al. Circulation, 2009;119:2426-34; Jiménez-Jáimez J. Am. J. Cardiol. 2015;116(6):894-9Mellor G. Circ Cardiovasc Genet. 2017;10(3); Kapplinger JD. Circ Genom Precis Med. 2018;11(2):e001424. Alterations affecting the same amino acid (p.A2387V, c.7160C>T and p.A2387P, c.7159G>C) have also been identified in CPVT cohorts (Bagattin A et al. Clin. Chem., 2004;50:1148-55; Haugaa KH et al. Europace, 2010;12:417-23). 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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.78		Gain of disorder (P = 0.124);.;
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.57
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs794728753; hg19: chr1-237804240; COSMIC: COSV100770091;