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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 13, 2019
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:: RCV004556715.1

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]

Condition(s)

Name:: Malignant hyperthermia, susceptibility to
Synonyms:: Malignant hyperthermia susceptibility
Identifiers:: MONDO: MONDO:0800188; MedGen: C5437603; OMIM: PS145600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005045776	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 13, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005045776

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 13, 2019)

unknown

clinical testing

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

Help

Summary from all submissions

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

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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV005045776.1

#	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, 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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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