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NM_000540.3(RYR1):c.6730C>T (p.Arg2244Trp) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 18, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003995868.2

Allele description [Variation Report for NM_000540.3(RYR1):c.6730C>T (p.Arg2244Trp)]

NM_000540.3(RYR1):c.6730C>T (p.Arg2244Trp)

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.6730C>T (p.Arg2244Trp)
HGVS:
  • NC_000019.10:g.38496475C>T
  • NG_008866.1:g.67776C>T
  • NM_000540.3:c.6730C>TMANE SELECT
  • NM_001042723.2:c.6730C>T
  • NP_000531.2:p.Arg2244Trp
  • NP_000531.2:p.Arg2244Trp
  • NP_001036188.1:p.Arg2244Trp
  • LRG_766t1:c.6730C>T
  • LRG_766:g.67776C>T
  • LRG_766p1:p.Arg2244Trp
  • NC_000019.9:g.38987115C>T
  • NM_000540.2:c.6730C>T
Protein change:
R2244W
Links:
dbSNP: rs772753793
NCBI 1000 Genomes Browser:
rs772753793
Molecular consequence:
  • NM_000540.3:c.6730C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.6730C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
10

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
SCV004820893All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Dec 18, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown10not providednot provided108544not providedclinical testing

Citations

PubMed

Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum.

Maclennan DH, Zvaritch E.

Biochim Biophys Acta. 2011 May;1813(5):948-64. doi: 10.1016/j.bbamcr.2010.11.009. Epub 2010 Nov 27. Review.

PubMed [citation]
PMID:
21118704

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 All of Us Research Program, National Institutes of Health, SCV004820893.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided10not providednot providedclinical testing PubMed (2)

Description

This missense variant replaces arginine with tryptophan at codon 2244 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 18/282504 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 provided10not providednot providednot provided

Last Updated: Sep 29, 2024