NM_001035.3(RYR2):c.506G>A (p.Arg169Gln) AND Catecholaminergic polymorphic ventricular tachycardia 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002513428.3

Allele description [Variation Report for NM_001035.3(RYR2):c.506G>A (p.Arg169Gln)]

NM_001035.3(RYR2):c.506G>A (p.Arg169Gln)

Gene:

RYR2:ryanodine receptor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_001035.3(RYR2):c.506G>A (p.Arg169Gln)

Other names:

p.R169Q:CGA>CAA

HGVS:

NC_000001.11:g.237377365G>A
NG_008799.3:g.340182G>A
NM_001035.3:c.506G>AMANE SELECT
NP_001026.2:p.Arg169Gln
LRG_402t1:c.506G>A
LRG_402:g.340182G>A
LRG_402p1:p.Arg169Gln
NC_000001.10:g.237540665G>A
NG_008799.2:g.339964G>A
NM_001035.2:c.506G>A
c.506G>A

Protein change:

R169Q

Links:

dbSNP: rs397516539

NCBI 1000 Genomes Browser:

rs397516539

Molecular consequence:

NM_001035.3:c.506G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Catecholaminergic polymorphic ventricular tachycardia 1
Synonyms:: VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1, WITH OR WITHOUT ATRIAL DYSFUNCTION AND/OR DILATED CARDIOMYOPATHY; Stress-induced polymorphic ventricular tachycardia; VENTRICULAR TACHYCARDIA, STRESS-INDUCED POLYMORPHIC 1
Identifiers:: MONDO: MONDO:0011484; MedGen: C1631597; Orphanet: 3286; OMIM: 604772

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002239421	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 18, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16517285, 23595086, 26114861, 28492532
SCV003921884	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002239421

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 18, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003921884

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2022)

de novo

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel mutation (Arg169Gln) of the cardiac ryanodine receptor gene causing exercise-induced bidirectional ventricular tachycardia.

Hsueh CH, Weng YC, Chen CY, Lin TK, Lin YH, Lai LP, Lin JL.

Int J Cardiol. 2006 Apr 4;108(2):276-8.

PubMed [citation]

PMID:: 16517285

Genetic background of catecholaminergic polymorphic ventricular tachycardia in Japan.

Kawamura M, Ohno S, Naiki N, Nagaoka I, Dochi K, Wang Q, Hasegawa K, Kimura H, Miyamoto A, Mizusawa Y, Itoh H, Makiyama T, Sumitomo N, Ushinohama H, Oyama K, Murakoshi N, Aonuma K, Horigome H, Honda T, Yoshinaga M, Ito M, Horie M.

Circ J. 2013;77(7):1705-13. Epub 2013 Apr 18. Erratum in: Circ J. 2020;84(11):2124-2126.

PubMed [citation]

PMID:: 23595086

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002239421.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV003921884.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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