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NM_000540.3(RYR1):c.14051T>C (p.Phe4684Ser) 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:
RCV003997314.2

Allele description [Variation Report for NM_000540.3(RYR1):c.14051T>C (p.Phe4684Ser)]

NM_000540.3(RYR1):c.14051T>C (p.Phe4684Ser)

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.14051T>C (p.Phe4684Ser)
HGVS:
  • NC_000019.10:g.38573229T>C
  • NG_008866.1:g.144530T>C
  • NM_000540.3:c.14051T>CMANE SELECT
  • NM_001042723.2:c.14036T>C
  • NP_000531.2:p.Phe4684Ser
  • NP_000531.2:p.Phe4684Ser
  • NP_001036188.1:p.Phe4679Ser
  • LRG_766t1:c.14051T>C
  • LRG_766:g.144530T>C
  • LRG_766p1:p.Phe4684Ser
  • NC_000019.9:g.39063869T>C
  • NC_000019.9:g.39063869T>C
  • NM_000540.2(RYR1):c.14051T>C
  • NM_000540.2:c.14051T>C
  • P21817:p.Phe4684Ser
  • p.(Phe4684Ser)
Protein change:
F4679S
Links:
UniProtKB: P21817#VAR_045747; dbSNP: rs193922864
NCBI 1000 Genomes Browser:
rs193922864
Molecular consequence:
  • NM_000540.3:c.14051T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.14036T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV004836350All of Us Research Program, National Institutes of Health
criteria provided, single submitter

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

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility.

Monnier N, Kozak-Ribbens G, Krivosic-Horber R, Nivoche Y, Qi D, Kraev N, Loke J, Sharma P, Tegazzin V, Figarella-Branger D, Roméro N, Mezin P, Bendahan D, Payen JF, Depret T, Maclennan DH, Lunardi J.

Hum Mutat. 2005 Nov;26(5):413-25.

PubMed [citation]
PMID:
16163667

Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia.

Galli L, Orrico A, Lorenzini S, Censini S, Falciani M, Covacci A, Tegazzin V, Sorrentino V.

Hum Mutat. 2006 Aug;27(8):830.

PubMed [citation]
PMID:
16835904
See all PubMed Citations (4)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004836350.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

This missense variant replaces phenylalanine with serine at codon 4684 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.85, PMID: 27666373). This variant occurs in the C-terminal region (a.a. 4,631-4,991) of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with a positive in vitro contracture test and a positive family or personal history of a malignant hyperthermia event (PMID: 16163667). It has also been observed in an individual with a positive in vitro contracture test and an uncertain personal or family history of a malignant hyperthermia event (PMID: 16835904). This variant has not been identified 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 provided1not providednot providednot provided

Last Updated: Oct 26, 2024