U.S. flag

An official website of the United States government

NM_000540.3(RYR1):c.7048G>A (p.Ala2350Thr) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Mar 17, 2021
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:
RCV000148806.12

Allele description [Variation Report for NM_000540.3(RYR1):c.7048G>A (p.Ala2350Thr)]

NM_000540.3(RYR1):c.7048G>A (p.Ala2350Thr)

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.7048G>A (p.Ala2350Thr)
Other names:
NM_000540.3(RYR1):c.7048G>A
HGVS:
  • NC_000019.10:g.38499655G>A
  • NG_008866.1:g.70956G>A
  • NM_000540.3:c.7048G>AMANE SELECT
  • NM_001042723.2:c.7048G>A
  • NP_000531.2:p.Ala2350Thr
  • NP_000531.2:p.Ala2350Thr
  • NP_001036188.1:p.Ala2350Thr
  • LRG_766t1:c.7048G>A
  • LRG_766:g.70956G>A
  • LRG_766p1:p.Ala2350Thr
  • NC_000019.9:g.38990295G>A
  • NM_000540.2:c.7048G>A
  • P21817:p.Ala2350Thr
  • p.(Ala2350Thr)
Protein change:
A2350T
Links:
PharmGKB: 1445400232PA164749136; PharmGKB: 1445400232PA449461; PharmGKB: 1445400232PA449845; PharmGKB: 1445400232PA450106; PharmGKB: 1445400232PA450434; PharmGKB: 1445400232PA451341; PharmGKB: 1445400232PA451522; UniProtKB: P21817#VAR_045721; dbSNP: rs193922802
NCBI 1000 Genomes Browser:
rs193922802
Molecular consequence:
  • NM_000540.3:c.7048G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.7048G>A - 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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000190545CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation
no assertion criteria provided
Pathogenic
(Jun 1, 2014)
germlineresearch

SCV001816202ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen
reviewed by expert panel

(ClinGen MHS ACMG Specifications V1)
Pathogenic
(Mar 17, 2021)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch, curation

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190545.1

#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, SCV001816202.1

#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 Alanine with Threonine at codon 2350 of the RYR1 protein, p.(Ala2350Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 19 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 17 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:11525881, PMID:12434264, and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:11525881). An ex vivo study in myotubes from a single patient also showed increased sensitivity to RYR1 agonists, (PMID:15210166). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 7 individuals PP1_Strong (PMID:11525881, PMID:25960145). A REVEL score >0.85 (0.952) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate.

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

Last Updated: Jul 15, 2024