NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg) AND RYR1-related disorder

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 24, 2024
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:: RCV000551243.17

Allele description [Variation Report for NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)]

NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)

Gene:

RYR1:ryanodine receptor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)

Other names:

NM_000540.3(RYR1):c.7300G>A

HGVS:

NC_000019.10:g.38499993G>A
NG_008866.1:g.71294G>A
NM_000540.3:c.7300G>AMANE SELECT
NM_001042723.2:c.7300G>A
NP_000531.2:p.Gly2434Arg
NP_000531.2:p.Gly2434Arg
NP_001036188.1:p.Gly2434Arg
LRG_766t1:c.7300G>A
LRG_766:g.71294G>A
LRG_766p1:p.Gly2434Arg
NC_000019.9:g.38990633G>A
NM_000540.2:c.7300G>A
P21817:p.Gly2434Arg
p.(Gly2434Arg)

Protein change:

G2434R; GLY2434ARG

Links:

PharmGKB: 1183705812PA164749136; PharmGKB: 1183705812PA449461; PharmGKB: 1183705812PA449845; PharmGKB: 1183705812PA450106; PharmGKB: 1183705812PA450434; PharmGKB: 1183705812PA451341; PharmGKB: 1183705812PA451522; UniProtKB: P21817#VAR_005605; OMIM: 180901.0007; dbSNP: rs121918593

NCBI 1000 Genomes Browser:

rs121918593

Molecular consequence:

NM_000540.3:c.7300G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7300G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RYR1-related disorder
Synonyms:: RYR1-Related Disorders; RYR1-related condition
Identifiers:: MedGen: CN239331

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000660024	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 7849712, 10484775, 11668625, 19648156, 23842196, 24433488, 9030597, 9334205, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000660024

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (9)
[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

Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees.

Keating KE, Quane KA, Manning BM, Lehane M, Hartung E, Censier K, Urwyler A, Klausnitzer M, Muller CR, Heffron JJ, et al.

Hum Mol Genet. 1994 Oct;3(10):1855-8.

PubMed [citation]

PMID:: 7849712

Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test.

Brandt A, Schleithoff L, Jurkat-Rott K, Klingler W, Baur C, Lehmann-Horn F.

Hum Mol Genet. 1999 Oct;8(11):2055-62.

PubMed [citation]

PMID:: 10484775

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000660024.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2434 of the RYR1 protein (p.Gly2434Arg). This variant is present in population databases (rs121918593, gnomAD 0.008%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 7849712, 9030597, 10484775, 11668625, 19648156, 23842196, 24433488). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly2433Arg. ClinVar contains an entry for this variant (Variation ID: 12970). 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 RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9030597, 9334205). 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

Last Updated: Nov 3, 2024

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