NM_000540.3(RYR1):c.11708G>A (p.Arg3903Gln) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 6, 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:: RCV001580388.4

Allele description [Variation Report for NM_000540.3(RYR1):c.11708G>A (p.Arg3903Gln)]

NM_000540.3(RYR1):c.11708G>A (p.Arg3903Gln)

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.11708G>A (p.Arg3903Gln)

HGVS:

NC_000019.10:g.38543365G>A
NG_008866.1:g.114666G>A
NM_000540.3:c.11708G>AMANE SELECT
NM_001042723.2:c.11693G>A
NP_000531.2:p.Arg3903Gln
NP_000531.2:p.Arg3903Gln
NP_001036188.1:p.Arg3898Gln
LRG_766t1:c.11708G>A
LRG_766:g.114666G>A
LRG_766p1:p.Arg3903Gln
NC_000019.9:g.39034005G>A
NM_000540.2(RYR1):c.11708G>A
NM_000540.2:c.11708G>A
p.(Arg3903Gln)
p.Arg3903Gln

Protein change:

R3898Q

Links:

dbSNP: rs148399313

NCBI 1000 Genomes Browser:

rs148399313

Molecular consequence:

NM_000540.3:c.11708G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.11693G>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
SCV001810071	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	reviewed by expert panel (RYR1-MHS Interpretation Guidelines V2)	Likely pathogenic (Apr 6, 2023)	germline	curation	Citation Link,
SCV004816219	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Oct 2, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16835904, 19191333, 20681998, 30236257, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001810071

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(RYR1-MHS Interpretation Guidelines V2)

Likely pathogenic
(Apr 6, 2023)

germline

curation

Citation Link,

SCV004816219

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Oct 2, 2023)

germline

clinical testing

PubMed (5)
[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	3	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia.

Galli L, Orrico A, Lorenzini S, Censini S, Falciani M, Covacci A, Tegazzin V, Sorrentino V.

Hum Mutat. 2006 Aug;27(8):830.

PubMed [citation]

PMID:: 16835904

Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes.

Zullo A, Klingler W, De Sarno C, Ferrara M, Fortunato G, Perrotta G, Gravino E, Di Noto R, Lehmann-Horn F, Melzer W, Salvatore F, Carsana A.

Hum Mutat. 2009 Apr;30(4):E575-90. doi: 10.1002/humu.20991.

PubMed [citation]

PMID:: 19191333

See all PubMed Citations (5)

Details of each submission

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen, SCV001810071.2

#	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 3903 of the RYR1 protein, p.(Arg3903Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000026, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight 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:20681998, PMID:24433488, PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.97) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4, PP3_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 All of Us Research Program, National Institutes of Health, SCV004816219.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces arginine with glutamine at codon 3903 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals and families affected with malignant hyperthermia susceptibility (PMID: 16835904, 19191333, 20681998, 30236257). This variant has been identified in 3/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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