NM_001035.3(RYR2):c.11863C>A (p.Gln3955Lys) AND Catecholaminergic polymorphic ventricular tachycardia 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 2, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002471405.1

Allele description [Variation Report for NM_001035.3(RYR2):c.11863C>A (p.Gln3955Lys)]

NM_001035.3(RYR2):c.11863C>A (p.Gln3955Lys)

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.11863C>A (p.Gln3955Lys)

HGVS:

NC_000001.11:g.237778753C>A
NG_008799.3:g.741570C>A
NM_001035.3:c.11863C>AMANE SELECT
NP_001026.2:p.Gln3955Lys
LRG_402t1:c.11863C>A
LRG_402:g.741570C>A
LRG_402p1:p.Gln3955Lys
NC_000001.10:g.237942053C>A
NM_001035.2:c.11863C>A

Protein change:

Q3955K

Links:

dbSNP: rs1558393802

NCBI 1000 Genomes Browser:

rs1558393802

Molecular consequence:

NM_001035.3:c.11863C>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; 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
SCV002767430	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12459180, 23549275, 27646203, 29477366, 30696458, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002767430

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 2, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations.

Tiso N, Salamon M, Bagattin A, Danieli GA, Argenton F, Bortolussi M.

Biochem Biophys Res Commun. 2002 Dec 13;299(4):594-8.

PubMed [citation]

PMID:: 12459180

Clinical utility gene card for: Catecholaminergic polymorphic ventricular tachycardia (CPVT).

Napolitano C, Bloise R, Memmi M, Priori SG.

Eur J Hum Genet. 2014 Jan;22(1). doi: 10.1038/ejhg.2013.55. Epub 2013 Apr 3. No abstract available.

PubMed [citation]

PMID:: 23549275
PMCID:: PMC3865399

See all PubMed Citations (6)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767430.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 (CPVT; MIM#604772) (PMIDs: 12459180, 27646203, 29477366). (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 glutamine to lysine. (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; PMID: 30696458). (SP) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. The p.(Gln3395Glu) variant has been classified once as likely pathogenic, primarily because it has been observed by Invitae in-house as de novo in CPVT individuals while the p.(Gln3395His) variant has been classified as a VUS (ClinVar). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation 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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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