rs397516539

Positions:

• chr1-237377365-G-A
• chr1-237377365-G-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.506G>A​(p.Arg169Gln) 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 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:6
• Conservation: PhyloP100: 10.0

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, 0.983
• PP5: Variant 1-237377365-G-A is Pathogenic according to our data. Variant chr1-237377365-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237377365-G-A is described in Lovd as [Pathogenic]. Variant chr1-237377365-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.506G>A	p.Arg169Gln	missense_variant	8/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.506G>A	p.Arg169Gln	missense_variant	8/105	1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000660292.2	c.506G>A	p.Arg169Gln	missense_variant	8/106			ENSP00000499787
RYR2	ENST00000659194.3	c.506G>A	p.Arg169Gln	missense_variant	8/105			ENSP00000499653
RYR2	ENST00000609119.2	c.506G>A	p.Arg169Gln	missense_variant, NMD_transcript_variant	8/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2014	p.Arg169Gln (CGA>CAA):c.506 G>A in exon 8 of the RYR2 gene (NM_001035.2). The Arg169Gln mutation in the RYR2 gene has been reported previously in an 18 year old female with exercised induced ventricular tachycardia and was absent from 100 reference alleles (Hsueh C et al., 2006). In addition, the NHLBI ESP Exome Variant Server reports Arg169Gln was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Arg169Gln resides in the N-terminal domain, one of three mutation hot spots, in the RYR2 gene (Medeiros-Domingo A et al., 2009). Structural studies indicate that Arg169Gln leads to destabilization of the beta8-beta9 loop in this region of the protein (Lobo P et al., 2009). Mutations in nearby codons (Pro164Ser, Arg176Gln) have been reported in association with polymorphic ventricular tachycardia and ARVD further supporting the functional importance of this region of the protein. In summary, Arg169Gln in the RYR2 gene is interpreted as a disease-causing mutation. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is characterized by syncope, typically beginning in the first decade of life, which may be triggered by physical activity or intense emotion. In patients with CPVT, stress-induced release of catecholamines causes a dysfunction of the calcium-ion channel in the myocytes (De La Fuente et al., 2008; Napolitano C et al., 2012; Priori S et al., 2002). CPVT is primarily caused by autosomal dominant mutations in the RYR2 and KCNJ2 genes. Less commonly, CPVT is caused by autosomal recessive mutations in the CASQ2 gene (Napolitano C et al., 2012). Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in CPVT panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) and left ventricular non-compaction (PMID: 12459180, 27646203, 29477366, 31875585, 33500567). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The variant p.(Arg169Leu) has been reported pathogenic in ClinVar, and de novo in a patient with CPVT (PMID: 26114861). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is multiply reported pathogenic in ClinVar and the literature in individuals with CPVT or LVNC with atypical CPVT, several of whom were de novo (PMID: 16517285, 23595086, 26114861, 29453246, 31875585). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been found to result in reduced threshold for overload-induced Ca2+ release from the sarcoplasmic reticulum and increased fractional Ca2+ release, by in vitro studies (PMID: 31875585). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed; by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 18, 2023	For these reasons, this variant has been classified as Pathogenic. 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: 43801). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 16517285, 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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the RYR2 protein (p.Arg169Gln). -

Catecholaminergic polymorphic ventricular tachycardia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 27, 2013

The Arg169Gln variant in RYR2 has been reported in 3 Asian individuals with CPVT , was reported to occur de novo in one of these individuals, and was absent from 200 control chromosomes (Hsueh 2006, Ge 2012, Kawamura 2013). This variant has been identified by our laboratory in 1 Caucasian individual with LVNC and bidire ctional VT, and was not identified in large population studies. Arginine (Arg) a t position 169 is highly conserved in mammals and across evolutionarily distant species and computational analyses (AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg169Gln variant may impact the protein, which raises the possibility that a change at this position might not be tolerated. Additionally, this variant is located in a conserved domain of the RYR2 protein that may be critical for prot ein interactions and where other variants are clustered (Amador 2009, Lobo 2009) . In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2019

The p.R169Q pathogenic mutation (also known as c.506G>A), located in coding exon 8 of the RYR2 gene, results from a G to A substitution at nucleotide position 506. The arginine at codon 169 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in patients with suspected or reported catecholaminergic polymorphic ventricular tachycardia (CPVT), and has also been reported as occurring de novo in two pediatric cases from a CPVT cohort who experienced cardiac arrest (Hsueh CH et al. Int J Cardiol. 2006;108:276-8; Kawamura M et al. Circ J. 2013;77:1705-13; Ohno S. PLoS ONE. 2015;10(6):e0131517). Structural analyses have suggested that this alteration occurs in a variant clustering domain and may break ionic interactions (Lobo PA et al. Structure. 2009;17:1505-14; Amador FJ et al. Proc Natl Acad Sci. U.S.A. 2009;106:11040-4). 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	0.93
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.90		Loss of phosphorylation at S170 (P = 0.0968);.;
MVP		1.0
MPC		0.64
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.89
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516539; hg19: chr1-237540665; COSMIC: COSV63686290;