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NM_020549.5(CHAT):c.605T>G (p.Met202Arg) AND Congenital myasthenic syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 7, 2022
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:
RCV002469176.1

Allele description [Variation Report for NM_020549.5(CHAT):c.605T>G (p.Met202Arg)]

NM_020549.5(CHAT):c.605T>G (p.Met202Arg)

Gene:
CHAT:choline O-acetyltransferase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q11.23
Genomic location:
Preferred name:
NM_020549.5(CHAT):c.605T>G (p.Met202Arg)
HGVS:
  • NC_000010.11:g.49620520T>G
  • NG_011797.1:g.16426T>G
  • NM_001142929.2:c.251T>G
  • NM_001142933.2:c.359T>G
  • NM_001142934.2:c.251T>G
  • NM_020549.5:c.605T>GMANE SELECT
  • NM_020984.4:c.251T>G
  • NM_020985.4:c.251T>G
  • NM_020986.4:c.251T>G
  • NP_001136401.2:p.Met84Arg
  • NP_001136405.2:p.Met120Arg
  • NP_001136406.2:p.Met84Arg
  • NP_065574.3:p.Met202Arg
  • NP_065574.4:p.Met202Arg
  • NP_066264.4:p.Met84Arg
  • NP_066265.4:p.Met84Arg
  • NP_066266.4:p.Met84Arg
  • NC_000010.10:g.50828566T>G
  • NM_020549.4:c.605T>G
Protein change:
M120R
Links:
dbSNP: rs376808313
NCBI 1000 Genomes Browser:
rs376808313
Molecular consequence:
  • NM_001142929.2:c.251T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001142933.2:c.359T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001142934.2:c.251T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020549.5:c.605T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020984.4:c.251T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020985.4:c.251T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020986.4:c.251T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Congenital myasthenic syndrome (CMS)
Identifiers:
MONDO: MONDO:0018940; MeSH: D020294; MedGen: C0751882; OMIM: PS601462

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002766422Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Nov 7, 2022)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Functional consequences and structural interpretation of mutations of human choline acetyltransferase.

Shen XM, Crawford TO, Brengman J, Acsadi G, Iannaconne S, Karaca E, Khoury C, Mah JK, Edvardson S, Bajzer Z, Rodgers D, Engel AG.

Hum Mutat. 2011 Nov;32(11):1259-67. doi: 10.1002/humu.21560. Epub 2011 Sep 23.

PubMed [citation]
PMID:
21786365
PMCID:
PMC3196808

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002766422.1

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

Description

Variant summary: CHAT c.605T>G (p.Met202Arg) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant alters a highly conserved nucleotide located in the active-site tunnel of the protein (Shen_2011). The variant allele was found at a frequency of 6e-05 in 251406 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHAT causing Congenital Myasthenic Syndrome (6e-05 vs 0.00079), allowing no conclusion about variant significance. c.605T>G has been reported in the literature in an individual affected with ChAT deficiency (Shen_2011). Additionally, functional assessment of the recombinantly-expressed mutant showed the variant to drastically reduce the catalytic efficiency of the protein (Shen_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified as pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Jun 17, 2024