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NM_000540.3(RYR1):c.131G>A (p.Arg44His) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:
Uncertain significance (3 submissions)
Last evaluated:
Apr 7, 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:
RCV000148813.7

Allele description [Variation Report for NM_000540.3(RYR1):c.131G>A (p.Arg44His)]

NM_000540.3(RYR1):c.131G>A (p.Arg44His)

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.131G>A (p.Arg44His)
Other names:
NM_000540.2(RYR1):c.131G>A
HGVS:
  • NC_000019.10:g.38440830G>A
  • NG_008866.1:g.12131G>A
  • NM_000540.3:c.131G>AMANE SELECT
  • NM_001042723.2:c.131G>A
  • NP_000531.2:p.Arg44His
  • NP_000531.2:p.Arg44His
  • NP_001036188.1:p.Arg44His
  • LRG_766t1:c.131G>A
  • LRG_766:g.12131G>A
  • LRG_766p1:p.Arg44His
  • NC_000019.9:g.38931470G>A
  • NC_000019.9:g.38931470G>A
  • NM_000540.2:c.131G>A
  • p.(Arg44His)
Protein change:
R44H
Links:
dbSNP: rs139161723
NCBI 1000 Genomes Browser:
rs139161723
Molecular consequence:
  • NM_000540.3:c.131G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.131G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000190552CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation
no assertion criteria provided
Uncertain significance
(Jun 1, 2014) 		germlineresearch

SCV001816147ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen
reviewed by expert panel

(RYR1-MHS Interpretation Guidelines V2)		Uncertain significance
(Apr 7, 2023) 		germlinecuration

Citation Link,

SCV004833975All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Jul 19, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing, research, 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

Mutations in RYR1 in malignant hyperthermia and central core disease.

Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P.

Hum Mutat. 2006 Oct;27(10):977-89. Review.

PubMed [citation]
PMID:
16917943
See all PubMed Citations (5)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190552.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen, SCV001816147.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot 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 histidine at codon 44 of the RYR1 protein, p.(Arg44His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000066, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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_Supporting (PMID:30236257 ). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1, (PMID: 21118704). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004833975.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

This missense variant replaces arginine with histidine at codon 44 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in three individuals affected with malignant hyperthermia susceptibility or with a history of a malignant hyperthermia event (PMID: 16835904, 16917943, 30236257, ClinVar: SCV000659808.3). This variant has been identified in 3/242016 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.130C>T (p.Arg44Cys), is considered pathogenic (ClinVar Variation ID: 133045), indicating that Arg at this position is important for RYR1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 16, 2024