NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln) AND RYR1-related disorder

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 22, 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:: RCV001380753.12

Allele description [Variation Report for NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)]

NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)

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.14210G>A (p.Arg4737Gln)

Other names:

NM_000540.2(RYR1):c.14210G>A

HGVS:

NC_000019.10:g.38577955G>A
NG_008866.1:g.149256G>A
NM_000540.3:c.14210G>AMANE SELECT
NM_001042723.2:c.14195G>A
NP_000531.2:p.Arg4737Gln
NP_000531.2:p.Arg4737Gln
NP_001036188.1:p.Arg4732Gln
LRG_766t1:c.14210G>A
LRG_766:g.149256G>A
LRG_766p1:p.Arg4737Gln
NC_000019.9:g.39068595G>A
NM_000540.2:c.14210G>A
P21817:p.Arg4737Gln
p.(Arg4737Gln)

Protein change:

R4732Q

Links:

UniProtKB: P21817#VAR_045749; dbSNP: rs193922868

NCBI 1000 Genomes Browser:

rs193922868

Molecular consequence:

NM_000540.3:c.14210G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14195G>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
SCV001578910	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 22, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16163667, 18564801, 19648156, 25960145, 27558158, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001578910

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 22, 2023)

germline

clinical testing

PubMed (6)
[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

Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility.

Monnier N, Kozak-Ribbens G, Krivosic-Horber R, Nivoche Y, Qi D, Kraev N, Loke J, Sharma P, Tegazzin V, Figarella-Branger D, Roméro N, Mezin P, Bendahan D, Payen JF, Depret T, Maclennan DH, Lunardi J.

Hum Mutat. 2005 Nov;26(5):413-25.

PubMed [citation]

PMID:: 16163667

Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots.

Gillies RL, Bjorksten AR, Davis M, Du Sart D.

Anaesth Intensive Care. 2008 May;36(3):391-403.

PubMed [citation]

PMID:: 18564801

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001578910.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4737 of the RYR1 protein (p.Arg4737Gln). This variant is present in population databases (rs193922868, gnomAD 0.0009%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 16163667, 18564801, 19648156, 25960145). ClinVar contains an entry for this variant (Variation ID: 133061). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). 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 10, 2024

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