NM_001035.3(RYR2):c.14368C>T (p.Arg4790Ter) AND Catecholaminergic polymorphic ventricular tachycardia 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 28, 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:: RCV002545594.10

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]

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
SCV001543005	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 35439358, 37492947, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001543005

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 28, 2023)

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

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

RyR2 C-terminal truncating variants identified in patients with arrhythmic phenotypes exert a dominant negative effect through formation of wildtype-truncation heteromers.

Tian S, Zhong X, Wang H, Wei J, Guo W, Wang R, Paul Estillore J, Napolitano C, Duff HH, Ilhan E, Knight LM, Lloyd MS, Roberts JD, Priori SG, Chen SRW.

Biochem J. 2023 Sep 13;480(17):1379-1395. doi: 10.1042/BCJ20230254.

PubMed [citation]

PMID:: 37492947

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001543005.4

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

Description

This sequence change creates a premature translational stop signal (p.Arg4790*) in the RYR2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RYR2 cause disease. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal dominant RYR2-related conditions (PMID: 35439358). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1044450). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects RYR2 function (PMID: 35439358, 37492947). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Oct 26, 2024

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