rs121918600

Variant names:

• chr1-237791441-C-T
• rs121918600
• NM_001035.3:c.13489C>T

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 50 publications found

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

ENSG00000296715 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• 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, 0.99
• PP5: Variant 1-237791441-C-T is Pathogenic according to our data. Variant chr1-237791441-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12957.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	c.13489C>T	p.Arg4497Cys	missense_variant	Exon 93 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.13489C>T	p.Arg4497Cys	missense_variant	Exon 93 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.13507C>T	p.Arg4503Cys	missense_variant	Exon 94 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*4581C>T		non_coding_transcript_exon_variant	Exon 92 of 104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*4581C>T		3_prime_UTR_variant	Exon 92 of 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32986

American (AMR) AF: 0.0000255 AC: 1 AN: 39146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25486

East Asian (EAS) AF: 0.00 AC: 0 AN: 38746

South Asian (SAS) AF: 0.00 AC: 0 AN: 81576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1084270

Other (OTH) AF: 0.00 AC: 0 AN: 58828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0183214), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

Oct 11, 2023

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 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. -

Jan 16, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:2

Jan 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Aug 03, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_moderate, PP2, PP3, PM2_supporting, PS3, PS4 -

Cardiomyopathy Pathogenic:1

Jul 19, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Nov 25, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		3.1
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
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121918600; hg19: chr1-237954741; COSMIC: COSV63706542; COSMIC: COSV63706542;