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NM_000540.3(RYR1):c.10042C>T (p.Arg3348Cys) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:
Uncertain significance (4 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:
RCV000377005.10

Allele description [Variation Report for NM_000540.3(RYR1):c.10042C>T (p.Arg3348Cys)]

NM_000540.3(RYR1):c.10042C>T (p.Arg3348Cys)

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.10042C>T (p.Arg3348Cys)
Other names:
NM_000540.2(RYR1):c.10042C>T; p.Arg3348Cys
HGVS:
  • NC_000019.10:g.38519237C>T
  • NG_008866.1:g.90538C>T
  • NM_000540.3:c.10042C>TMANE SELECT
  • NM_001042723.2:c.10042C>T
  • NP_000531.2:p.Arg3348Cys
  • NP_000531.2:p.Arg3348Cys
  • NP_001036188.1:p.Arg3348Cys
  • LRG_766t1:c.10042C>T
  • LRG_766:g.90538C>T
  • LRG_766p1:p.Arg3348Cys
  • NC_000019.9:g.39009877C>T
  • NM_000540.2:c.10042C>T
Protein change:
R3348C
Links:
dbSNP: rs118204421
NCBI 1000 Genomes Browser:
rs118204421
Molecular consequence:
  • NM_000540.3:c.10042C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.10042C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
20

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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000412700Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)
Uncertain significance
(Apr 28, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV002318981ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(RYR1-MHS Interpretation Guidelines V2)
Uncertain significance
(Apr 6, 2023)
germlinecuration

Citation Link,

SCV004358176Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Mar 13, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004820964All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain Significance
(Dec 1, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown20not providednot provided108544not providedclinical testing, curation

Citations

PubMed

Novel double and single ryanodine receptor 1 variants in two Austrian malignant hyperthermia families.

Kaufmann A, Kraft B, Michalek-Sauberer A, Weindlmayr M, Kress HG, Steinboeck F, Weigl LG.

Anesth Analg. 2012 May;114(5):1017-25. doi: 10.1213/ANE.0b013e31824a95ad. Epub 2012 Mar 13.

PubMed [citation]
PMID:
22415532

Genetic epidemiology of malignant hyperthermia in the UK.

Miller DM, Daly C, Aboelsaod EM, Gardner L, Hobson SJ, Riasat K, Shepherd S, Robinson RL, Bilmen JG, Gupta PK, Shaw MA, Hopkins PM.

Br J Anaesth. 2018 Oct;121(4):944-952. doi: 10.1016/j.bja.2018.06.028. Epub 2018 Aug 17.

PubMed [citation]
PMID:
30236257
PMCID:
PMC6208294
See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000412700.3

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

Description

The RYR1 c.10042C>T (p.Arg3348Cys) variant has been reported in one study in which it was found in two individuals from the same family (Kaufmann et al. 2012). The index individual was compound heterozygous for the p.Arg3348Cys variant and a second missense variant and was found to be susceptible to malignant hyperthermia based on an in vitro contracture test. In addition, her mother was heterozygous for the p.Arg3348Cys variant and exhibited malignant hyperthermia equivocal to halothane based on an in vitro contracture test. The index individual's sister was heterozygous for the other missense variant and was also susceptible to malignant hyperthermia. In the presence of halothane, cells that carried the p.Arg3348Cys variant were three times more sensitive than control cells, and in cells that carried both variants, the reaction sensitivity was increased even further. The p.Arg3348Cys variant was absent from 105 controls and is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Arg3348Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for malignant hyperthermia susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen, SCV002318981.2

#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 cysteine at codon 3348 of the RYR1 protein, p.(Arg3348Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000132, 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) (PMID:30236257), PS4_Supporting. 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 of 0.603 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting.

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

From Color Diagnostics, LLC DBA Color Health, SCV004358176.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This missense variant replaces arginine with cysteine at codon 3348 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). A functional study in patient-derived muscle cells showed cells carrying this variant were more sensitive to caffeine and halothane, but not 4-CmC, than cells carrying wild-type RYR1 (PMID: 22415532). This variant has been reported in two families affected with malignant hyperthermia susceptibility (PMID: 22415532, 30236257). One family also carried a pathogenic variant in the RYR1 gene that could explain the observed phenotype (PMID: 22415532). This variant has been identified in 19/282350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

From All of Us Research Program, National Institutes of Health, SCV004820964.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided20not providednot providedclinical testing PubMed (3)

Description

This missense variant replaces arginine with cysteine at codon 3348 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). A functional study in patient-derived muscle cells showed cells carrying this variant were more sensitive to caffeine and halothane, but not 4-CmC, than cells carrying wild-type RYR1 (PMID: 22415532). This variant has been reported in two families affected with malignant hyperthermia susceptibility (PMID: 22415532, 30236257). One family also carried a pathogenic variant in the RYR1 gene that could explain the observed phenotype (PMID: 22415532). This variant has been identified in 19/282350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided20not providednot providednot provided

Last Updated: Oct 8, 2024