NM_001035.3(RYR2):c.14876G>A (p.Arg4959Gln) AND Catecholaminergic polymorphic ventricular tachycardia 1

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Oct 15, 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:: RCV000445354.16

Allele description [Variation Report for NM_001035.3(RYR2):c.14876G>A (p.Arg4959Gln)]

NM_001035.3(RYR2):c.14876G>A (p.Arg4959Gln)

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.14876G>A (p.Arg4959Gln)

Other names:

p.R4959Q:CGG>CAG; NM_001035.2(RYR2):c.14876G>A(p.Arg4959Gln)

HGVS:

NC_000001.11:g.237832619G>A
NG_008799.3:g.795436G>A
NM_001035.3:c.14876G>AMANE SELECT
NP_001026.2:p.Arg4959Gln
LRG_402t1:c.14876G>A
LRG_402:g.795436G>A
LRG_402p1:p.Arg4959Gln
NC_000001.10:g.237995919G>A
NG_008799.2:g.795218G>A
NM_001035.2:c.14876G>A
Q92736:p.Arg4959Gln
p.R4959Q

Protein change:

R4959Q

Links:

UniProtKB: Q92736#VAR_023696; dbSNP: rs794728811

NCBI 1000 Genomes Browser:

rs794728811

Molecular consequence:

NM_001035.3:c.14876G>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
SCV000494584	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 27, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000803500	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 31, 2018)	unknown	curation	PubMed (5) [See all records that cite these PMIDs] 14571276, 16188589, 27231019, 15721128, 25741868
SCV000831162	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 15, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 14571276, 15721128, 16188589, 29453246, 28492532
SCV001369496	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 28, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002583382	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	no assertion criteria provided	Pathogenic (Feb 1, 2022)	germline	clinical testing

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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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Caucasian	germline	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Implantable Loop Recorder Monitoring for Refining Management of Children With Inherited Arrhythmia Syndromes.

Avari Silva JN, Bromberg BI, Emge FK, Bowman TM, Van Hare GF.

J Am Heart Assoc. 2016 May 26;5(6). doi:pii: e003632. 10.1161/JAHA.116.003632.

PubMed [citation]

PMID:: 27231019
PMCID:: PMC4937287

Molecular genetics of exercise-induced polymorphic ventricular tachycardia: identification of three novel cardiac ryanodine receptor mutations and two common calsequestrin 2 amino-acid polymorphisms.

Laitinen PJ, Swan H, Kontula K.

Eur J Hum Genet. 2003 Nov;11(11):888-91.

PubMed [citation]

PMID:: 14571276

See all PubMed Citations (7)

Details of each submission

From Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre, SCV000494584.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	not provided	not provided	not provided	research	PubMed (1)

Description

The patient was diagnosed with typical polymorphic ventricular tachycardia at the age of 12 followed by ICD implantation. No relatives are available for genetic testing.

#	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

From SIB Swiss Institute of Bioinformatics, SCV000803500.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

Description

This variant is interpreted as a Likely Pathogenic, for Ventricular tachycardia, catecholaminergic polymorphic, 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:14571276,16188589,27231019,15721128). PP1-Moderate => PP1 upgraded in strength to Moderate (PMID:15721128).

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

From Invitae, SCV000831162.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4959 of the RYR2 protein (p.Arg4959Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with catecholaminergic polymorphic ventricular tachycardia, and RYR2-related disease (PMID: 14571276, 15721128, 16188589, 29453246). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201365). 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. For these reasons, this variant has been classified as Pathogenic.

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001369496.2

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP1-S,PM2,PP3.

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

From Clinical Genetics Laboratory, University Hospital Schleswig-Holstein, SCV002583382.1

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

#	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: Apr 20, 2024

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