NM_001035.3(RYR2):c.14368C>T (p.Arg4790Ter) AND Catecholaminergic polymorphic ventricular tachycardia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 3, 2023
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:: RCV004005224.2

Allele description [Variation Report for NM_001035.3(RYR2):c.14368C>T (p.Arg4790Ter)]

NM_001035.3(RYR2):c.14368C>T (p.Arg4790Ter)

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.14368C>T (p.Arg4790Ter)

HGVS:

NC_000001.11:g.237808970C>T
NG_008799.3:g.771787C>T
NM_001035.3:c.14368C>TMANE SELECT
NP_001026.2:p.Arg4790Ter
LRG_402t1:c.14368C>T
LRG_402:g.771787C>T
LRG_402p1:p.Arg4790Ter
NC_000001.10:g.237972270C>T

Protein change:

R4790*

Links:

dbSNP: rs1660964820

NCBI 1000 Genomes Browser:

rs1660964820

Molecular consequence:

NM_001035.3:c.14368C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Catecholaminergic polymorphic ventricular tachycardia (CVPT)
Synonyms:: Familial polymorphic ventricular tachycardia; Catecholamine-induced polymorphic ventricular tachycardia; Polymorphic catecholergic ventricular tachycardia
Identifiers:: MONDO: MONDO:0017990; MedGen: C5574922; Orphanet: 3286; OMIM: PS604772

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004822372	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35439358, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004822372

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 3, 2023)

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	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling.

Hopton C, Tijsen AJ, Maizels L, Arbel G, Gepstein A, Bates N, Brown B, Huber I, Kimber SJ, Newman WG, Venetucci L, Gepstein L.

Physiol Rep. 2022 Apr;10(8):e15265. doi: 10.14814/phy2.15265. Erratum in: Physiol Rep. 2022 Aug;10(15):e15428. doi: 10.14814/phy2.15428.

PubMed [citation]

PMID:: 35439358
PMCID:: PMC9017975

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004822372.1

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

Description

This variant changes 1 nucleotide in exon 100 of the RYR2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with cardiac arrest and syncopal episodes associated with emotional stress, as well as in another seven family members including two who were symptomatic (PMID: 35439358). Cardiomyocytes differentiated from induced human pluripotent stem cells generated from the proband showed a significant reduction of RYR2 at both mRNA and protein levels and marked intracellular calcium transient abnormalities, which were significantly reduced by allele-specific shRNA (PMID: 35439358). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The role of loss-of-function RYR2 truncation variants in cardiovascular disorders is not clearly understood. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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