NM_000540.3(RYR1):c.14693T>C (p.Ile4898Thr) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 22, 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:: RCV000013844.15

Allele description [Variation Report for NM_000540.3(RYR1):c.14693T>C (p.Ile4898Thr)]

NM_000540.3(RYR1):c.14693T>C (p.Ile4898Thr)

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.14693T>C (p.Ile4898Thr)

Other names:

NM_000540.3(RYR1):c.14693T>C

HGVS:

NC_000019.10:g.38584989T>C
NG_008866.1:g.156290T>C
NM_000540.3:c.14693T>CMANE SELECT
NM_001042723.2:c.14678T>C
NP_000531.2:p.Ile4898Thr
NP_000531.2:p.Ile4898Thr
NP_001036188.1:p.Ile4893Thr
LRG_766t1:c.14693T>C
LRG_766:g.156290T>C
LRG_766p1:p.Ile4898Thr
NC_000019.9:g.39075629T>C
NM_000540.2:c.14693T>C
NM_000540.3:c.14693T>C
P21817:p.Ile4898Thr
p.(Ile4898Thr)

Protein change:

I4893T; ILE4898THR

Links:

UniProtKB: P21817#VAR_045771; OMIM: 180901.0012; dbSNP: rs118192170

Molecular consequence:

NM_000540.3:c.14693T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14678T>C - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000928375	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 27, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003930278	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen MHS ACMG Specifications V2)	Uncertain significance (May 22, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000928375

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 27, 2018)

germline

clinical testing

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

SCV003930278

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen MHS ACMG Specifications V2)

Uncertain significance
(May 22, 2023)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

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 Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV000928375.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PM1, PM2, PP3, PP4, PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen, SCV003930278.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The ClinGen RYR1-MHS variant curation expert panel is focused on assessing variants in RYR1 for pathogenicity as related to 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 Isoleucine with Threonine at codon 4898 of the RYR1 protein, p.(Ile4898Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in individuals with a personal or family history of an MH episode or central core disease but without sufficient information to consider the reports for informing PS4 in relation to MHS inherited in an autosomal dominant pattern (PMID: 10097181, 11709545, 12565913, 16621918 and others). Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID:10097181). Additional functional studies were published for this variant that did not show statistical differences in resting Ca2+ and sarcoplasmic reticulum Ca2+ content, however, those assays were not considered standard assays for variant interpretation in regard to MHS by the ClinGen RYR1 VCEP (PMID:11274444, PMID: 12642598). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance in relation to MHS inherited in an autosomal dominant pattern. Criteria implemented: PM1_Sup, PP3_Moderate, BS3_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 12, 2026

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