NM_000540.3(RYR1):c.103T>C (p.Cys35Arg) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 18, 2021
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:: RCV001588932.12

Allele description [Variation Report for NM_000540.3(RYR1):c.103T>C (p.Cys35Arg)]

NM_000540.3(RYR1):c.103T>C (p.Cys35Arg)

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.103T>C (p.Cys35Arg)

Other names:

NM_000540.3(RYR1):c.103T>C

HGVS:

NC_000019.10:g.38440802T>C
NG_008866.1:g.12103T>C
NM_000540.3:c.103T>CMANE SELECT
NM_001042723.2:c.103T>C
NP_000531.2:p.Cys35Arg
NP_000531.2:p.Cys35Arg
NP_001036188.1:p.Cys35Arg
LRG_766t1:c.103T>C
LRG_766:g.12103T>C
LRG_766p1:p.Cys35Arg
NC_000019.9:g.38931442T>C
NM_000540.2:c.103T>C
P21817:p.Cys35Arg
p.(Cys35Arg)

Protein change:

C35R

Links:

PharmGKB: 1445400910PA164749136; PharmGKB: 1445400910PA449461; PharmGKB: 1445400910PA449845; PharmGKB: 1445400910PA450106; PharmGKB: 1445400910PA450434; PharmGKB: 1445400910PA451341; PharmGKB: 1445400910PA451522; UniProtKB: P21817#VAR_005589; dbSNP: rs193922747

NCBI 1000 Genomes Browser:

rs193922747

Molecular consequence:

NM_000540.3:c.103T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.103T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV001816162	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen	reviewed by expert panel (ClinGen MHS ACMG Specifications V1)	Pathogenic (Mar 18, 2021)	germline	curation	Citation Link,
SCV004820701	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9066328, 9334205, 16163667, 17710899, 20681998, 21118704, 26115329, 31841587, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001816162

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen

reviewed by expert panel

(ClinGen MHS ACMG Specifications V1)

Pathogenic
(Mar 18, 2021)

germline

curation

Citation Link,

SCV004820701

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred.

Lynch PJ, Krivosic-Horber R, Reyford H, Monnier N, Quane K, Adnet P, Haudecoeur G, Krivosic I, McCarthy T, Lunardi J.

Anesthesiology. 1997 Mar;86(3):620-6.

PubMed [citation]

PMID:: 9066328

Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease.

Tong J, Oyamada H, Demaurex N, Grinstein S, McCarthy TV, MacLennan DH.

J Biol Chem. 1997 Oct 17;272(42):26332-9.

PubMed [citation]

PMID:: 9334205

See all PubMed Citations (9)

Details of each submission

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen, SCV001816162.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not 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 cysteine with arginine at codon 35 of the RYR1 protein, p.(Cys35Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:17710899, PMID:20681998, PMID:9066328). Functional studies in HEK293 cells show conflicting data regarding sensitivity to RYR1 agonists, PS3/BS3 were not implemented (PMID:9334205, PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 11 individuals, PP1_Strong (PMID:9066328). A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate, PP1_Strong. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386).

#	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

From All of Us Research Program, National Institutes of Health, SCV004820701.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces cysteine with arginine at codon 35 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). Functional studies in HEK293 cells are conflicted in the impact of this variant on sensitivity to caffeine and halothane compared to cells expressing wild-type RYR1 (PMID: 9334205, 26115329, 31841587). This variant has been reported in at least four unrelated families or individuals affected with malignant hyperthermia susceptibility (PMID: 9066328, 16163667, 17710899, 20681998). It has been shown that this variant segregates with the malignant hyperthermia susceptibility phenotype in one family (PMID: 9066328). This variant has been identified in 1/237252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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