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NM_000540.3(RYR1):c.7291G>T (p.Asp2431Tyr) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:
Likely pathogenic (2 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:
RCV001802868.5

Allele description [Variation Report for NM_000540.3(RYR1):c.7291G>T (p.Asp2431Tyr)]

NM_000540.3(RYR1):c.7291G>T (p.Asp2431Tyr)

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.7291G>T (p.Asp2431Tyr)
Other names:
NM_000540.2(RYR1):c.7291G>T
HGVS:
  • NC_000019.10:g.38499984G>T
  • NG_008866.1:g.71285G>T
  • NM_000540.3:c.7291G>TMANE SELECT
  • NM_001042723.2:c.7291G>T
  • NP_000531.2:p.Asp2431Tyr
  • NP_000531.2:p.Asp2431Tyr
  • NP_001036188.1:p.Asp2431Tyr
  • LRG_766t1:c.7291G>T
  • LRG_766:g.71285G>T
  • LRG_766p1:p.Asp2431Tyr
  • NC_000019.9:g.38990624G>T
  • NM_000540.2:c.7291G>T
Protein change:
D2431Y
Links:
dbSNP: rs193922810
NCBI 1000 Genomes Browser:
rs193922810
Molecular consequence:
  • NM_000540.3:c.7291G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.7291G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002047608ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(RYR1-MHS Interpretation Guidelines V2)		Likely pathogenic
(Apr 7, 2023) 		germlinecuration

Citation Link,

SCV002503772Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Mar 30, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Genetic variation in RYR1 and malignant hyperthermia phenotypes.

Carpenter D, Robinson RL, Quinnell RJ, Ringrose C, Hogg M, Casson F, Booms P, Iles DE, Halsall PJ, Steele DS, Shaw MA, Hopkins PM.

Br J Anaesth. 2009 Oct;103(4):538-48. doi: 10.1093/bja/aep204. Epub 2009 Jul 31.

PubMed [citation]
PMID:
19648156

A genetic mystery in malignant hyperthermia 'solved'?

Schiemann AH, Bjorksten AR, Gillies RL, Hockey BM, Ball C, Pollock N, Bulger T, Stowell KM.

Br J Anaesth. 2018 Sep;121(3):681-682. doi: 10.1016/j.bja.2018.05.051. Epub 2018 Jun 20. No abstract available.

PubMed [citation]
PMID:
30115273
See all PubMed Citations (4)

Details of each submission

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen, SCV002047608.3

#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 aspartic acid with tyrosine at codon 2431 of the RYR1 protein, p.(Asp2431Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three 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_Moderate (PMID:30236257, PMID:30115273). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:30115273). Another variant assessed as likely pathogenic occurs at this codon, p.(Asp2431Asn), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1_Supporting (PMID:30236257). A REVEL score >0.85 (0.964) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PM5_Supporting, PP1, PP3_Moderate.

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

From Molecular Genetics, Royal Melbourne Hospital, SCV002503772.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change is predicted to replace aspartic acid with tyrosine at codon 2431 of the RYR1 protein (p.(Asp2431Tyr)). The aspartic acid residue is invariant across species (100 vertebrates, UCSC), and there is a large physicochemical difference between aspartic acid and tyrosine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.0). The prevalence of the variant in an affected cohort is significantly increased compared with the prevalence of a relevant low risk population (PMID: 30236257). The variant is associated with a clinical reaction consistent with malignant hyperthermia (MH) under anaesthesia and confirmed by a positive in vitro contracture tests, and segregates with MH susceptibility in multiple families (PMID: 19648156, 30115273, 30236257). A well-established in vitro functional study is supportive of a gain of function effect on intracellular calcium release for the variant (PMID: 30115273). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PS4, PM2, PP1, PP3, PP4.

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

Last Updated: May 19, 2024