rs121918597

Positions:

• chr1-237634937-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001035.3(RYR2):​c.6737C>T​(p.Ser2246Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S2246S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.91

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 1-237634937-C-T is Pathogenic according to our data. Variant chr1-237634937-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237634937-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.6737C>T	p.Ser2246Leu	missense_variant	44/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.6737C>T	p.Ser2246Leu	missense_variant	44/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.6737C>T	p.Ser2246Leu	missense_variant	44/106
RYR2	ENST00000659194.3	c.6737C>T	p.Ser2246Leu	missense_variant	44/105
RYR2	ENST00000609119.2	c.6737C>T	p.Ser2246Leu	missense_variant, NMD_transcript_variant	44/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 02, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 17, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 12837242, 16239587, 18092949, 19226252, 21768539). 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: 12954). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 11208676, 16843546, 19926015, 23595086, 26114861). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2246 of the RYR2 protein (p.Ser2246Leu). -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 20, 2020

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2021

Not observed at significant frequency 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 by causing abnormal channel function (Wehrens et al., 2003; Jiang et al., 2005; Suetomi et al., 2011); Is 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); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 12954; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27114410, 18092949, 16843546, 30403697, 31112425, 30640888, 19226252, 12837242, 21768539, 11208676, 15544015, 24025405, 19926015, 26114861, 12919952, 29427818, 28202948, 12093772, 29434162, 29453248, 29453246, 30975432, 30302938, 31995186, 23595086, 16239587, 26582918) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

The p.S2246L pathogenic mutation (also known as c.6737C>T), located in coding exon 44 of the RYR2 gene, results from a C to T substitution at nucleotide position 6737. The serine at codon 2246 is replaced by leucine, an amino acid with dissimilar properties. This mutation has been reported in several unrelated individuals reported to have catecholaminergic polymorphic ventricular tachycardia (CPVT), features of CPVT, or sudden arrest/death, including several cases in whom this mutation occurred de novo (Priori SG et al. Circulation, 2001 Jan;103:196-2001; Priori SG et al. Circulation, 2002 Jul;106:69-74; Aizawa Y et al. Int J Cardiol, 2007 Mar;116:263-5; Ohno S et al. PLoS One, 2015 Jun;10:e0131517; Halvorsen M et al. Proc Natl Acad Sci U S A, 2021 Dec;118; Anderson JH et al. Circ Cardiovasc Genet, 2016 Jun;9:259-65; Song JS et al. J Hum Genet, 2017 Jun;62:615-620; Roston TM et al. PLoS One, 2018 Nov;13:e0205925; Kawamura M et al. Circ J, 2013 Apr;77:1705-13; Chiu SN et al. Arch Dis Child, 2022 Jan;107:41-46; Eitoku T et al. HeartRhythm Case Rep, 2023 Mar;9:152-155). In vitro studies indicate this variant impacts protein function by way of increased calcium sensitivity (Wehrens XH et al. Cell, 2003 Jun;113:829-40; Jones PP et al. Biochem J, 2008 May;412:171-8). Furthermore, a knock-in mouse model expressing this variant recapitulated CPVT phenotype (Suetomi T et al. Circulation, 2011 Aug;124:682-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.84		Loss of disorder (P = 0.0457);.;
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.72
gMVP		0.90

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: rs121918597; hg19: chr1-237798237; COSMIC: COSV63698185;