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NM_000540.3(RYR1):c.14915C>T (p.Thr4972Ile) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Aug 6, 2024
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:
RCV000209974.5

Allele description [Variation Report for NM_000540.3(RYR1):c.14915C>T (p.Thr4972Ile)]

NM_000540.3(RYR1):c.14915C>T (p.Thr4972Ile)

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.14915C>T (p.Thr4972Ile)
HGVS:
  • NC_000019.10:g.38586137C>T
  • NG_008866.1:g.157438C>T
  • NM_000540.3:c.14915C>TMANE SELECT
  • NM_001042723.2:c.14900C>T
  • NP_000531.2:p.Thr4972Ile
  • NP_000531.2:p.Thr4972Ile
  • NP_001036188.1:p.Thr4967Ile
  • LRG_766t1:c.14915C>T
  • LRG_766:g.157438C>T
  • LRG_766p1:p.Thr4972Ile
  • NC_000019.9:g.39076777C>T
  • NM_000540.2:c.14915C>T
Protein change:
T4967I
Links:
dbSNP: rs199866740
NCBI 1000 Genomes Browser:
rs199866740
Molecular consequence:
  • NM_000540.3:c.14915C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.14900C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
16

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
SCV000265752Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq
criteria provided, single submitter

(Gonsalves et al. 2013)		Uncertain significance
(Jul 1, 2013) 		unknownresearch

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

SCV004816281All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Aug 6, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown16not providednot provided143475not providedclinical testing
not providedunknownunknown1not providednot providednot providednot providedresearch

Citations

PubMed

Using exome data to identify malignant hyperthermia susceptibility mutations.

Gonsalves SG, Ng D, Johnston JJ, Teer JK, Stenson PD, Cooper DN, Mullikin JC, Biesecker LG; NISC Comparative Sequencing Program.

Anesthesiology. 2013 Nov;119(5):1043-53. doi: 10.1097/ALN.0b013e3182a8a8e7.

PubMed [citation]
PMID:
24195946
PMCID:
PMC4077354

MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples.

Savarese M, Di Fruscio G, Mutarelli M, Torella A, Magri F, Santorelli FM, Comi GP, Bruno C, Nigro V.

Acta Neuropathol Commun. 2014 Sep 11;2:100. doi: 10.1186/s40478-014-0100-3.

PubMed [citation]
PMID:
25214167
PMCID:
PMC4172906
See all PubMed Citations (3)

Details of each submission

From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000265752.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot provided1not providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004816281.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided16not providednot providedclinical testing PubMed (2)

Description

This missense variant replaces threonine with isoleucine at codon 4972 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 limb-girdle muscular dystrophy (PMID: 25214167). This variant has been identified in 22/282792 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
1germlineunknown143475not providednot provided16not providednot providednot provided

Last Updated: May 16, 2025