NM_001035.3(RYR2):c.2350A>T (p.Ile784Phe) AND Catecholaminergic polymorphic ventricular tachycardia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 13, 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:: RCV003996747.2

Allele description [Variation Report for NM_001035.3(RYR2):c.2350A>T (p.Ile784Phe)]

NM_001035.3(RYR2):c.2350A>T (p.Ile784Phe)

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.2350A>T (p.Ile784Phe)

HGVS:

NC_000001.11:g.237500857A>T
NG_008799.3:g.463674A>T
NM_001035.2:c.2350A>T
NM_001035.3:c.2350A>TMANE SELECT
NP_001026.2:p.Ile784Phe
LRG_402t1:c.2350A>T
LRG_402:g.463674A>T
LRG_402p1:p.Ile784Phe
NC_000001.10:g.237664157A>T
NG_008799.2:g.463456A>T

Protein change:

I784F

Links:

dbSNP: rs794728729

NCBI 1000 Genomes Browser:

rs794728729

Molecular consequence:

NM_001035.3:c.2350A>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004814632	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33664309, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004814632

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 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	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes.

Touat-Hamici Z, Blancard M, Ma R, Lin L, Iddir Y, Denjoy I, Leenhardt A, Yuchi Z, Guicheney P.

Sci Rep. 2021 Mar 4;11(1):5243. doi: 10.1038/s41598-021-84373-9.

PubMed [citation]

PMID:: 33664309
PMCID:: PMC7970841

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, SCV004814632.1

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

Description

This missense variant replaces isoleucine with phenylalanine at codon 784 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant causes significant increase in calcium oscillation frequency and an enhanced store overload-induced calcium release in response to cAMP treatment in transfected HEK293 cells (PMID: 33664309). This study also showed that this variant causes a conformational change which impacts channel gating and also affects thermal stability resulting in a strong destabilizing effect. This variant has been reported in one individual who experienced sudden cardiac death after experiencing short-coupled torsade de pointes (PMID: 33664309). This variant has been identified in 2/249286 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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