NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Pathogenic (9 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:: RCV000013846.26

Allele description [Variation Report for NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)]

NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)

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.6617C>T (p.Thr2206Met)

Other names:

NM_000540.3(RYR1):c.6617C>T

HGVS:

NC_000019.10:g.38496283C>T
NG_008866.1:g.67584C>T
NM_000540.3:c.6617C>TMANE SELECT
NM_001042723.2:c.6617C>T
NP_000531.2:p.Thr2206Met
NP_000531.2:p.Thr2206Met
NP_001036188.1:p.Thr2206Met
LRG_766t1:c.6617C>T
LRG_766:g.67584C>T
LRG_766p1:p.Thr2206Met
NC_000019.9:g.38986923C>T
NM_000540.2:c.6617C>T
NM_000540.3:c.6617C>T
P21817:p.Thr2206Met
p.(Thr2206Met)

Protein change:

T2206M; THR2206MET

Links:

UniProtKB: P21817#VAR_005604; OMIM: 180901.0014; dbSNP: rs118192177

NCBI 1000 Genomes Browser:

rs118192177

Molecular consequence:

NM_000540.3:c.6617C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.6617C>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
SCV000034093	OMIM	no assertion criteria provided	risk factor (Aug 1, 2002)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 9497245, 12220451, 21514828
SCV001425408	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 21, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12220451, 16084090, 27586648, 25741868
SCV001434860	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 17, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001440599	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 28, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002318979	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	reviewed by expert panel (RYR1-MHS Interpretation Guidelines V2)	Pathogenic (Mar 14, 2022)	germline	curation	Citation Link,
SCV002583354	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	no assertion criteria provided	Pathogenic (Dec 1, 2021)	germline	clinical testing
SCV002764861	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Feb 19, 2021)	maternal	clinical testing	Citation Link,
SCV004358102	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9497245, 19919814, 25960145, 27586648, 30236257, 31206373, 25741868
SCV004820887	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (21) [See all records that cite these PMIDs] 9497245, 10484775, 11575529, 12059893, 12220451, 12434264, 15731587, 16163667, 17081152, 18505122, 21118704, 22696611, 23558838, 24433488, 25268394, 25735680, 25960145, 27586648, 30236257, 31559918, 25741868

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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	8	not provided	not provided	108544	not provided	clinical testing, curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene.

Dowling JJ, Lillis S, Amburgey K, Zhou H, Al-Sarraj S, Buk SJ, Wraige E, Chow G, Abbs S, Leber S, Lachlan K, Baralle D, Taylor A, Sewry C, Muntoni F, Jungbluth H.

Neuromuscul Disord. 2011 Jun;21(6):420-7. doi: 10.1016/j.nmd.2011.03.006. Epub 2011 Apr 22.

PubMed [citation]

PMID:: 21514828

Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders.

Treves S, Anderson AA, Ducreux S, Divet A, Bleunven C, Grasso C, Paesante S, Zorzato F.

Neuromuscul Disord. 2005 Oct;15(9-10):577-87. Review.

PubMed [citation]

PMID:: 16084090

See all PubMed Citations (25)

Details of each submission

From OMIM, SCV000034093.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

Malignant Hyperthermia, Susceptibility to, 1

In affected members of a family with malignant hyperthermia (MHS1; 145600), Manning et al. (1998) identified a heterozygous c.6617C-T transition in the RYR1 gene, resulting in a thr2206-to-met (T2206M) substitution.

Wehner et al. (2002) identified the T2206M mutation in patients with MHS. Myotubes derived from individuals with the T2206M mutation had an abnormal response of the intracellular calcium concentration to 4-chloro-m-cresol and to caffeine. In myotubes, the EC50 for 4-chloro-m-cresol and for caffeine was reduced strikingly, indicating that this mutation is pathogenic for malignant hyperthermia.

King-Denborough Syndrome

In a 6-year-old boy (patient 1) with King-Denborough syndrome (KDS; 619542), Dowling et al. (2011) identified heterozygosity for the c.6617C-T transition in exon 40 of the RYR1 gene, resulting in a T2206M substitution. The mutation was identified by RYR1 gene sequencing. Western blot analysis in patient muscle tissue showed an 84% reduction in RyR1 protein level compared to control.

#	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 Johns Hopkins Genomics, Johns Hopkins University, SCV001425408.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434860.1

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

Description

The c.6617C>T (p.Thr2206Met) variant in the RYR1 gene has been reported in multiple unrelated individuals affected with malignant hyperthermia (PMID 9497245, 12220451, 19648156) and is extremely rare in general population databases. Multiple independent in vitro experiments showed this variant is functionally damaging (PMID 12220451, 19648156, 27586648). Multiple in silico algorithms also predicted this p.Thr2206Met change to be deleterious. Therefore, this c.6617C>T (p.Thr2206Met) variant in the RYR1 gene is classified as pathogenic.

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001440599.3

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

Description

Criteria applied: PS4,PS3_MOD,PM5,PP3,PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	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, SCV002318979.1

#	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 threonine with methionine at codon 2206 of the RYR1 protein, p.(Thr2206Met). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, a frequency consistent with pathogenicity for MHS. This variant has been reported in 67 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 63 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 (PMID: 30236257, 12059893, 24433488, 23558838, 10484775, 25735680, 25960145, 16163667, 11575529, 12220451, 12434264, 15731587, 17081152, 18505122, 22696611, 9497245, 25268394, 31559918). This variant has been identified in at least three individuals with negative IVCT/CHCT results, BS2 (PMID: 30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID: 27586648). An ex vivo assay in patient derived myotubes from two related individuals showed an increased sensitivity to RYR1 agonists (PMID: 12220451). 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). Another variant that has been assessed as pathogenic occurs at this codon, p.(Thr2206Arg), PM5. This variant segregates with MHS in nine individuals, PP1_Strong (PMID: 12059893, 25960145). A REVEL score >0.85 (0.95) 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: PS4, PS3_Moderate, PM1_Supporting, PM5, PP1_Strong, PP3_Moderate, BS2.

#	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 Clinical Genetics Laboratory, University Hospital Schleswig-Holstein, SCV002583354.1

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

#	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 Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV002764861.1

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

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

From Color Diagnostics, LLC DBA Color Health, SCV004358102.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces threonine with methionine at codon 2206 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study in HEK293 cells showed that cells expressing this variant are more sensitive to the RYR1 agonist caffeine than cells expressing wild-type RYR1 (PMID: 27586648). This variant has been reported in multiple individuals and families affected with malignant hyperthermia susceptibility (PMID: 30236257, 31206373), and it has been shown that this variant segregates with malignant hyperthermia susceptibility in several families (PMID: 9497245, 19919814, 25960145). This variant has been identified in 6/282614 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004820887.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	PubMed (21)

Description

The c.6617C>T (p.Thr2206Met) variant in the RYR1 gene, that encodes ryanodine receptor 1, has been identified in numerous unrelated individuals (>50) with personal or family history of a malignant hyperthermia reaction and a positive in-vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID: 30236257, 12059893, 24433488, 23558838, 10484775, 25735680, 25960145, 16163667, 11575529, 12220451, 12434264, 15731587, 17081152, 18505122, 22696611, 9497245, 25268394, 31559918, ClinGen Review [ClinVar ID:12977]). This variant segregates with malignant hyperthermia syndrome (MHS) in nine individuals (PMID: 12059893, 25960145).This missense variant resides 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: 27586648). In-silico computational prediction tools suggest that the p.Thr2206Met variant may have deleterious effect on the protein function (REVEL score: 0.95). This variant has been interpreted as pathogenic by several submitters in ClinVar database including the ClinGen expert panel (ClinVar ID: 12977). Therefore, the c.6617C>T (p.Thr2206Met) variant in the RYR1 gene 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		8	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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