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NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 7, 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:
RCV004658961.1

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:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005161789Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(May 7, 2024) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test.

Brandt A, Schleithoff L, Jurkat-Rott K, Klingler W, Baur C, Lehmann-Horn F.

Hum Mol Genet. 1999 Oct;8(11):2055-62.

PubMed [citation]
PMID:
10484775
See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV005161789.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The c.6617C>T (p.T2206M) alteration is located in exon 40 (coding exon 40) of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 6617, causing the threonine (T) at amino acid position 2206 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (6/282614) total alleles studied. The highest observed frequency was 0.005% (1/19946) of East Asian alleles. This variant was reported in multiple unrelated individuals, as well as shown to segregate with disease in two large families, with a positive in vitro contracture test (IVCT) and/or a reported malignant hyperthermia event (Manning, 1998; Wang, 2008; Brandom, 2013; Klingler, 2014; Wehner, 2002). Another alteration at the same codon, c.6617C>G (p.T2206R), has been detected in individuals with clinical features of malignant hyperthermia susceptibility (Brandt, 1999; Yeh, 2005). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 24, 2024