rs121918600

Positions:

• chr1-237791441-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.13489C>T​(p.Arg4497Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,418,108 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R4497H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 3.13

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 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, 0.99
• PP5: Variant 1-237791441-C-T is Pathogenic according to our data. Variant chr1-237791441-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237791441-C-T is described in Lovd as [Pathogenic]. Variant chr1-237791441-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.13489C>T	p.Arg4497Cys	missense_variant	93/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.13489C>T	p.Arg4497Cys	missense_variant	93/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*4581C>T		non_coding_transcript_exon_variant	92/104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*4581C>T		3_prime_UTR_variant	92/104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1418108 Hom.: 0 Cov.: 27 AF XY: 0.00000142 AC XY: 1 AN XY: 702452

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000255

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 16, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4497 of the RYR2 protein (p.Arg4497Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant RYR2-related conditions (PMID: 11208676, 12093772, 15544015, 29434162, 29453246; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12957). 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. Experimental studies have shown that this missense change affects RYR2 function (PMID: 12169647, 12837242, 12919952, 15890976, 16339485, 20080988, 20538074, 26666913). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in channel dysfunction leading to arrhythmia (Jiang et al., 2002; Wehrens et al., 2003); Multiple other studies have utilized mouse models carrying the RYR2 R4496C variant (equivalent to R4497C human variant) to demonstrate that R4496C results in an increased propensity for triggered arrhythmia (Cerrone et al., 2005; Liu et al., 2006; Sedej et al., 2010); Reported in ClinVar (ClinVar Variant ID# 12957; ClinVar); 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: 19926015, 11208676, 19226252, 24025405, 27452199, 16828071, 15544015, 18006488, 12169647, 20080988, 16339485, 12919952, 16825580, 21742998, 16239587, 12093772, 29453246, 31737537, 12837242, 15890976, 29434162) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 03, 2022	PP1_moderate, PP2, PP3, PM2_supporting, PS3, PS4 -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 19, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2024

The p.R4497C pathogenic mutation (also known as c.13489C>T), located in coding exon 93 of the RYR2 gene, results from a C to T substitution at nucleotide position 13489. The arginine at codon 4497 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in individual(s) with features consistent with catecholaminergic polymorphic ventricular tachycardia (CPVT), was determined to be de novo in at least one individual, and segregated with disease in at least one family (Priori SG et al. Circulation 2001 Jan;10(2):196-200; Priori et al. Circulation 2002 Jul;113(7):829-40; Kawata H et al. Circ. J. 2016 Aug;80(9):1907-15). In multiple assays testing RYR2 function, this variant (studied mouse equivalent p.R4496C) showed functionally abnormal results and recapitulated CPVT phenotype (George CH et al. Circ. Res. 2003 Sept;93(6):531-40; Wehrens XH et al. Cell 2003 Jun;113(7):829-40; Cerrone M et al. Circ. Res. 2005 May;96(10):e77-82; Jiang D et al. Circ. Res. 2005 Nov;97(11):1173-81; Zissimopoulos S et al. Biochem. J. 2009 Apr;419(2):273-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant 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	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.1	D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.75
MutPred		0.94		Loss of MoRF binding (P = 0.0048);.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs121918600; hg19: chr1-237954741;