NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met) AND RYR1-related disorder

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 21, 2024
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:: RCV000655558.17

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:: RYR1-related disorder
Synonyms:: RYR1-Related Disorders; RYR1-related condition
Identifiers:: MedGen: CN239331

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000777489	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 9497245, 16835904, 19648156, 19919814, 23558838, 23919265, 24433488, 25960145, 12220451, 16084090, 27586648, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000777489

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 21, 2024)

germline

clinical testing

PubMed (12)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia.

Galli L, Orrico A, Lorenzini S, Censini S, Falciani M, Covacci A, Tegazzin V, Sorrentino V.

Hum Mutat. 2006 Aug;27(8):830.

PubMed [citation]

PMID:: 16835904

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000777489.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2206 of the RYR1 protein (p.Thr2206Met). This variant is present in population databases (rs118192177, gnomAD 0.003%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility and/or RYR1-related myopathy (PMID: 9497245, 12220451, 16835904, 19648156, 19919814, 23558838, 23919265, 24433488, 25960145; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12977). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 12220451, 16084090, 27586648). For these reasons, this variant has been 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

Last Updated: Sep 29, 2024

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