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NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met) AND Malignant hyperthermia of anesthesia

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Feb 19, 2021
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000606881.14

Allele description [Variation Report for NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)]

NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)

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.6617C>T (p.Thr2206Met)
Other names:
NM_000540.3(RYR1):c.6617C>T
HGVS:
  • NC_000019.10:g.38496283C>T
  • NG_008866.1:g.67584C>T
  • NM_000540.3:c.6617C>TMANE SELECT
  • NM_001042723.2:c.6617C>T
  • NP_000531.2:p.Thr2206Met
  • NP_000531.2:p.Thr2206Met
  • NP_001036188.1:p.Thr2206Met
  • LRG_766t1:c.6617C>T
  • LRG_766:g.67584C>T
  • LRG_766p1:p.Thr2206Met
  • NC_000019.9:g.38986923C>T
  • NM_000540.2:c.6617C>T
  • NM_000540.3:c.6617C>T
  • P21817:p.Thr2206Met
  • p.(Thr2206Met)
Protein change:
T2206M; THR2206MET
Links:
UniProtKB: P21817#VAR_005604; OMIM: 180901.0014; dbSNP: rs118192177
NCBI 1000 Genomes Browser:
rs118192177
Molecular consequence:
  • NM_000540.3:c.6617C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.6617C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
4

Condition(s)

Name:
Malignant hyperthermia of anesthesia
Synonyms:
Hyperthermia of anesthesia; Anesthesic-triggered malignant hyperthermia
Identifiers:
MONDO: MONDO:0018493; MedGen: C0024591; Human Phenotype Ontology: HP:0034733

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000712440Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Pathogenic
(Feb 19, 2021) 		germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV001370553Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(May 5, 2020)
Condition: Malignant hyperthermia susceptibility		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown44not providednot providednot providedclinical testing

Citations

PubMed

Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test.

Brandt A, Schleithoff L, Jurkat-Rott K, Klingler W, Baur C, Lehmann-Horn F.

Hum Mol Genet. 1999 Oct;8(11):2055-62.

PubMed [citation]
PMID:
10484775

Genotype-phenotype correlations in recessive RYR1-related myopathies.

Amburgey K, Bailey A, Hwang JH, Tarnopolsky MA, Bonnemann CG, Medne L, Mathews KD, Collins J, Daube JR, Wellman GP, Callaghan B, Clarke NF, Dowling JJ.

Orphanet J Rare Dis. 2013 Aug 6;8:117. doi: 10.1186/1750-1172-8-117.

PubMed [citation]
PMID:
23919265
PMCID:
PMC3751094
See all PubMed Citations (15)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712440.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testing PubMed (13)

Description

The p.Thr2206Met variant in RYR1 has been reported in the heterozygous state in >30 individuals with malignant hyperthermia (MH) and segregated with disease in 6 relatives from 3 families (Manning 1998 PMID: 9497245, Rueffert 2002 PMID: 19919814, Carpenter 2009 PMID: 19648156, Sambuughin 2001 PMID: 11575529, Wehner 2002 PMID: 12220451, Alazami 2015 PMID: 25558065, Miller 2018 PMID: 30236257, Ibarra Moreno 2019 PMID: 31206373). It was also reported in the heterozygous state in at least 1 individual with multi-minicore myopathy and in the homozygous state in 1 individual with muscular dystrophy (Amburgey 2013 PMID: 23919265). Additionally, it has been reported by other clinical laboratories in ClinVar (Variation ID: 12977) and has been identified in 0.004% (5/129110) of European chromosomes and 0.005% (1/19446) of East Asian by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Thr2206Met variant may impact RYR1 protein function (Wehner 2002 PMID: 12220451, Murayama 2016 PMID: 27586648), and computational prediction tools and conservation analysis suggest that this variant may impact the protein. This variant lies in the central region of the protein and missense variants in this region are statistically more likely to be disease-associated (Maclennan 2011 PMID: 21118704). In summary, this variant meets criteria to be classified as pathogenic for MH in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM1, PP1_Moderate, PM2_Supporting, PP3, PS3_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided4not provided4not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001370553.1

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

Description

Variant summary: RYR1 c.6617C>T (p.Thr2206Met) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251224 control chromosomes (gnomAD). c.6617C>T has been reported in the literature in numerous individuals affected with Malignant Hyperthermia Susceptibility and was also shown to co-segregate with disease in families (e.g. Manning_1998, Carpenter_2009, Brandom_2013, Klinger_2014). Functional studies have shown the variant to disrupt cellular calcium homeostasis (e.g. Wehner_2002). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Nov 24, 2024