NM_000540.3(RYR1):c.6487C>T (p.Arg2163Cys) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 14, 2022
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:: RCV000013840.17

Allele description [Variation Report for NM_000540.3(RYR1):c.6487C>T (p.Arg2163Cys)]

NM_000540.3(RYR1):c.6487C>T (p.Arg2163Cys)

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.6487C>T (p.Arg2163Cys)

Other names:

NM_000540.3(RYR1):c.6487C>T

HGVS:

NC_000019.10:g.38494564C>T
NG_008866.1:g.65865C>T
NM_000540.3:c.6487C>TMANE SELECT
NM_001042723.2:c.6487C>T
NP_000531.2:p.Arg2163Cys
NP_000531.2:p.Arg2163Cys
NP_001036188.1:p.Arg2163Cys
LRG_766t1:c.6487C>T
LRG_766:g.65865C>T
LRG_766p1:p.Arg2163Cys
NC_000019.9:g.38985204C>T
NM_000540.2:c.6487C>T
P21817:p.Arg2163Cys
p.(Arg2163Cys)

Protein change:

R2163C; ARG2163CYS

Links:

PharmGKB: 1183705797PA164749136; PharmGKB: 1183705797PA449461; PharmGKB: 1183705797PA449845; PharmGKB: 1183705797PA450106; PharmGKB: 1183705797PA450434; PharmGKB: 1183705797PA451341; PharmGKB: 1183705797PA451522; UniProtKB: P21817#VAR_005601; OMIM: 180901.0010; dbSNP: rs118192175

NCBI 1000 Genomes Browser:

rs118192175

Molecular consequence:

NM_000540.3:c.6487C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.6487C>T - 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
SCV000034087	OMIM	no assertion criteria provided	risk factor (Mar 1, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001816177	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen	reviewed by expert panel (RYR1-MHS Interpretation Guidelines V2)	Pathogenic (Mar 14, 2022)	germline	curation	Citation Link,
SCV004820883	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9497245, 9873004, 10484775, 21118704, 30236257, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000034087

OMIM

no assertion criteria provided

risk factor
(Mar 1, 1998)

germline

literature only

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

SCV001816177

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

reviewed by expert panel

(RYR1-MHS Interpretation Guidelines V2)

Pathogenic
(Mar 14, 2022)

germline

curation

Citation Link,

SCV004820883

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 6, 2024)

germline

clinical testing

PubMed (6)
[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	2	not provided	not provided	143475	not provided	clinical testing, curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation.

Manning BM, Quane KA, Ording H, Urwyler A, Tegazzin V, Lehane M, O'Halloran J, Hartung E, Giblin LM, Lynch PJ, Vaughan P, Censier K, Bendixen D, Comi G, Heytens L, Monsieurs K, Fagerlund T, Wolz W, Heffron JJ, Muller CR, McCarthy TV.

Am J Hum Genet. 1998 Mar;62(3):599-609.

PubMed [citation]

PMID:: 9497245
PMCID:: PMC1376943

Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels.

Tong J, McCarthy TV, MacLennan DH.

J Biol Chem. 1999 Jan 8;274(2):693-702.

PubMed [citation]

PMID:: 9873004

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000034087.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 unrelated families (D1 and D2), Manning et al. (1998) demonstrated that members with malignant hyperthermia (MHS1; 145600) had a heterozygous c.6487C-T transition in the RYR1 gene, resulting in an arg2163-to-cys (R2163C) substitution.

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

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen, SCV001816177.2

#	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 Arginine with Cysteine at codon 2163 of the RYR1 protein, p.(Arg2163Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, 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, three of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:10484775, PMID:30236257, PMID:9497245). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9873004). Another variant has been assessed as pathogenic at this codon, p.(Arg2163His), PM5 (PMID:30236257 ). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). This variant segregates with MHS in over 15 individuals PP1_Strong, (PMID:9497245, PMID:30236257, PMID:10484775). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP1_Strong, PP3_Moderate, BS2_Moderate.

#	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, SCV004820883.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (6)

Description

The c.6487C>T (p.Arg2163Cys) variant, located on the exon 39 of the RYR1 gene, replaces arginine with cysteine at codon 2163 of the RYR1 protein (p.Arg2163Cys). This missense change has been observed in 4 individuals with personal or family histories of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID:10484775, 30236257, 9497245). This variant was observed to segregate with malignant hyperthermia (MHS) in more than 15 individuals (PMID:10484775, 30236257, 9497245). To be noted, this variant has been identified in an MH normal individual with a negative IVCT/CHCT result, indicating incomplete penetrance (PMID: 30236257). This missense variant is located in a mutational hot spot region that contributes to MHS (PMID: 21118704). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID:9873004). Computational prediction (REVEL >0.85) suggests that this variant may have deleterious impact on protein structure and function. Additionally, an alteration affecting the same amino acid c.6488G>A (p.Arg2163His) was classified as pathogenic by the expert panel (ClinVar ID:12974). For these reasons, the c.6487C>T (p.Arg2163Cys) variant of RYR1 is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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