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NM_000540.3(RYR1):c.2654G>A (p.Arg885His) 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:
RCV000307765.12

Allele description [Variation Report for NM_000540.3(RYR1):c.2654G>A (p.Arg885His)]

NM_000540.3(RYR1):c.2654G>A (p.Arg885His)

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.2654G>A (p.Arg885His)
Other names:
NM_000540.2(RYR1):c.2654G>A; p.Arg885His; NM_001042723.2(RYR1):c.2654G>A
HGVS:
  • NC_000019.10:g.38463499G>A
  • NG_008866.1:g.34800G>A
  • NM_000540.3:c.2654G>AMANE SELECT
  • NM_001042723.2:c.2654G>A
  • NP_000531.2:p.Arg885His
  • NP_000531.2:p.Arg885His
  • NP_001036188.1:p.Arg885His
  • LRG_766t1:c.2654G>A
  • LRG_766:g.34800G>A
  • LRG_766p1:p.Arg885His
  • NC_000019.9:g.38954139G>A
  • NM_000540.2:c.2654G>A
  • NM_001042723.1:c.2654G>A
Protein change:
R885H
Links:
dbSNP: rs370634440
NCBI 1000 Genomes Browser:
rs370634440
Molecular consequence:
  • NM_000540.3:c.2654G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.2654G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
45

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
SCV000411943Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Uncertain significance
(Jan 13, 2018)
germlineclinical testing

Citation Link,

SCV001816142ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen
reviewed by expert panel

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

Citation Link,

SCV002564589Arcensus
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Feb 1, 2013)
germlineclinical testing

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

SCV004820781All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain Significance
(Feb 5, 2024)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown45not providednot provided108544not providedclinical testing, curation

Citations

PubMed

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000411943.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen, SCV001816142.2

#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 885 of the RYR1 protein (p.Arg885His). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00042, 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), however, the MAF in the SAS population in gnomAD does not allow PS4 to be utilized (PMID:30236257). 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 0.609 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none.

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

From Arcensus, SCV002564589.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004820781.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided45not providednot providedclinical testing PubMed (2)

Description

This missense variant replaces arginine with histidine at codon 885 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 46/280838 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 provided45not providednot providednot provided

Last Updated: Oct 20, 2024