NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 20, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV003231155.11

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]

Observations:

Condition(s)

Name:: Malignant hyperthermia, susceptibility to, 1 (MHS1)
Synonyms:: Anesthesia related hyperthermia; Malignant hyperpyrexia; Fulminating hyperpyrexia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007783; MedGen: C2930980; Orphanet: 423; OMIM: 145600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002047631	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen MHS ACMG Specifications V2)	Pathogenic (May 20, 2023)	germline	curation	Citation Link,
SCV004358222	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 5, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16163667, 18564801, 21118704, 24433488, 30236257, 36208971, 25741868
SCV004831690	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 11, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16163667, 18564801, 19648156, 21118704, 25960145, 27558158, 30236257, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002047631

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen MHS ACMG Specifications V2)

Pathogenic
(May 20, 2023)

germline

curation

Citation Link,

SCV004358222

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 5, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004831690

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 11, 2023)

germline

clinical testing

PubMed (8)
[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, curation

Citations

PubMed

Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study.

Klingler W, Heiderich S, Girard T, Gravino E, Heffron JJ, Johannsen S, Jurkat-Rott K, Rüffert H, Schuster F, Snoeck M, Sorrentino V, Tegazzin V, Lehmann-Horn F.

Orphanet J Rare Dis. 2014 Jan 16;9:8. doi: 10.1186/1750-1172-9-8.

PubMed [citation]

PMID:: 24433488
PMCID:: PMC3896768

Functional analysis of RYR1 variants in patients with confirmed susceptibility to malignant hyperthermia.

White R, Schiemann AH, Burling SM, Bjorksten A, Bulger T, Gillies R, Hopkins PM, Kamsteeg EJ, Machon RG, Massey S, Miller D, Perry M, Snoeck MMJ, Stephens J, Street N, van den Bersselaar LR, Stowell KM.

Br J Anaesth. 2022 Dec;129(6):879-888. doi: 10.1016/j.bja.2022.08.029. Epub 2022 Oct 6.

PubMed [citation]

PMID:: 36208971

See all PubMed Citations (10)

Details of each submission

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen, SCV002047631.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with glutamine at codon 4737 of the RYR1 protein, p.(Arg4737Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in 14 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:30236257, PMID:16163667, PMID:18564801, PMID:24433488, NZ MH investigation unit, MH Investigation Unit (MHIU), UHN, Toronto). This variant segregates with MHS in >6 meioses, PP1_Strong, (PMID:30236257 , PMID:18564801, MH Investigation Unit (MHIU), UHN, Toronto). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:36208971). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1_Supporting, PP1_Strong, PP3_Moderate, BS2_Moderate.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV004358222.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant replaces arginine with glutamine at codon 4737 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is located in a region of the RYR1 protein considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). A functional study has shown the mutant protein to exhibit hypersensitivity to an RYR1 agonist in calcium release assays (PMID: 36208971). This variant has been reported in over ten unrelated individuals affected with malignant hyperthermia susceptibility (PMID: 16163667, 18564801, 24433488, 30236257, 36208971). This variant has been shown to segregate with malignant hyperthermia susceptibility in 6 meioses in one family (PMID:18564801) and reported to segregate with disease in additional families (PMID: 30236257). Two related individuals who carry this variant have been reported to test negative in in vitro contracture tests (PMID: 30236257). This variant has been identified in 1/251402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg4737Trp, is known to be associated with malignant hyperthermia susceptibility (ClinVar variation ID: 133060), indicating that arginine at this position is important for RYR1 protein function. Based on the available evidence, this variant is 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

From All of Us Research Program, National Institutes of Health, SCV004831690.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

The c.14210G>A (p.Arg4737Gln) variant of the RYR1 gene replaces arginine with glutamine at codon 4737 of the RYR1 protein (p.Arg4737Gln). This missense change has been observed in more than 10 individuals with personal or family history of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 16163667, 18564801, 19648156, 25960145). This variant segregates with malignant hyperthermia syndrome (MHS) in more than 6 meioses (PMID:30236257, 18564801). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified. This variant is located at a mutational hot spot region that contributes to MHS (PMID: 21118704). Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). Computational prediction (REVEL=0.89 PMID: 27666373) suggests that this variant may have deleterious impact on protein structure and function. Alteration affecting the same amino acid, c.14209C>T (p.Arg4737Trp), was classified as likely pathogenic by the expert panel (ClinVar ID:133060). Therefore, this c.14210G>A (p.Arg4737Gln) variant of RYR1 gene is classified as pathogenic.

#	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: Nov 10, 2024

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