NM_001035.3(RYR2):c.13957G>T (p.Val4653Phe) AND Catecholaminergic polymorphic ventricular tachycardia 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 10, 2014
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000013827.31

Allele description [Variation Report for NM_001035.3(RYR2):c.13957G>T (p.Val4653Phe)]

NM_001035.3(RYR2):c.13957G>T (p.Val4653Phe)

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.13957G>T (p.Val4653Phe)

HGVS:

NC_000001.11:g.237798037G>T
NG_008799.3:g.760854G>T
NM_001035.3:c.13957G>TMANE SELECT
NP_001026.2:p.Val4653Phe
LRG_402t1:c.13957G>T
LRG_402:g.760854G>T
LRG_402p1:p.Val4653Phe
NC_000001.10:g.237961337G>T
NG_008799.2:g.760636G>T
NM_001035.2:c.13957G>T
Q92736:p.Val4653Phe

Protein change:

V4653F; VAL4653PHE

Links:

UniProtKB: Q92736#VAR_011403; OMIM: 180902.0008; dbSNP: rs121918604

NCBI 1000 Genomes Browser:

rs121918604

Molecular consequence:

NM_001035.3:c.13957G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000034074	OMIM	no assertion criteria provided	Pathogenic (Jun 29, 2004)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11157710, 15197150
SCV000057858	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 21454795, 20301466
SCV000207212	Blueprint Genetics	no assertion criteria provided	Likely pathogenic (Nov 10, 2014)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11157710, 15197150

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000034074

OMIM

no assertion criteria provided

Pathogenic
(Jun 29, 2004)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000057858

GeneReviews

no classification provided

not provided

unknown

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000207212

Blueprint Genetics

no assertion criteria provided

Likely pathogenic
(Nov 10, 2014)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis.

Priori SG, Chen SR.

Circ Res. 2011 Apr 1;108(7):871-83. doi: 10.1161/CIRCRESAHA.110.226845. Review.

PubMed [citation]

PMID:: 21454795
PMCID:: PMC3085083

Catecholaminergic Polymorphic Ventricular Tachycardia.

Napolitano C, Mazzanti A, Bloise R, Priori SG.

2004 Oct 14 [updated 2022 Jun 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301466

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000034074.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

Laitinen et al. (2001) reported a val4653-to-phe (V4653F) mutation in the RYR2 gene in a large Finnish family with a history of stress-induced ventricular tachycardia (CPVT1; 604772) and sudden unexplained death. This mutation was located in the carboxy-terminal part of the cardiac ryanodine receptor, which contains several membrane-spanning domains.

Lehnart et al. (2004) simulated the effects of exercise on mutant RYR2 channels using PKA phosphorylation. The V4653F mutant exhibited decreased binding of calstabin-2, a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, the mutant showed a significant gain-of-function defect consistent with leaky Ca(2+)-release channels and a significant rightward shift in the half-maximal inhibitory magnesium concentration. Treatment with an experimental drug enhanced the binding of calstabin-2 to RYR2 and normalized channel function.

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

From GeneReviews, SCV000057858.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

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

From Blueprint Genetics, SCV000207212.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

#	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		1	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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