NM_001035.3(RYR2):c.12458G>T (p.Ser4153Ile) AND Catecholaminergic polymorphic ventricular tachycardia 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 30, 2021
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:: RCV002567907.10

Allele description [Variation Report for NM_001035.3(RYR2):c.12458G>T (p.Ser4153Ile)]

NM_001035.3(RYR2):c.12458G>T (p.Ser4153Ile)

Genes:

LOC126806068:BRD4-independent group 4 enhancer GRCh37_chr1:237947411-237948610 [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.12458G>T (p.Ser4153Ile)

HGVS:

NC_000001.11:g.237784170G>T
NG_008799.3:g.746987G>T
NM_001035.3:c.12458G>TMANE SELECT
NP_001026.2:p.Ser4153Ile
LRG_402t1:c.12458G>T
LRG_402:g.746987G>T
LRG_402p1:p.Ser4153Ile
NC_000001.10:g.237947470G>T
NG_008799.2:g.746769G>T
NM_001035.2:c.12458G>T

Protein change:

S4153I

Links:

dbSNP: rs999437630

NCBI 1000 Genomes Browser:

rs999437630

Molecular consequence:

NM_001035.3:c.12458G>T - 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
SCV001409731	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 30, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26114861, 21652165, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001409731

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 30, 2021)

germline

clinical testing

PubMed (3)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Gender Differences in the Inheritance Mode of RYR2 Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia Patients.

Ohno S, Hasegawa K, Horie M.

PLoS One. 2015;10(6):e0131517. doi: 10.1371/journal.pone.0131517. Erratum in: PLoS One. 2021 Feb 19;16(2):e0243476. doi: 10.1371/journal.pone.0243476.

PubMed [citation]

PMID:: 26114861
PMCID:: PMC4482545

A novel mutation in the RYR2 gene leading to catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation: dose-dependent arrhythmia-event suppression by β-blocker therapy.

Kazemian P, Gollob MH, Pantano A, Oudit GY.

Can J Cardiol. 2011 Nov-Dec;27(6):870.e7-10. doi: 10.1016/j.cjca.2011.02.003. Epub 2011 Jun 8.

PubMed [citation]

PMID:: 21652165

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001409731.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 963024). This missense change has been observed in individual(s) with clinical features of catecholaminergic polymorphic ventricular tachycardia (PMID: 26114861). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 4153 of the RYR2 protein (p.Ser4153Ile). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ser4153 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 21652165), which suggests that this may be a clinically significant amino acid residue.

#	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

Last Updated: Nov 3, 2024

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