NM_020549.4(CHAT):c.1061C>T (p.Thr354Met) AND Familial infantile myasthenia

Clinical significance:Uncertain significance (Last evaluated: Aug 23, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000636628.4

Allele description [Variation Report for NM_020549.4(CHAT):c.1061C>T (p.Thr354Met)]

NM_020549.4(CHAT):c.1061C>T (p.Thr354Met)

Gene:
CHAT:choline O-acetyltransferase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q11.23
Genomic location:
Preferred name:
NM_020549.4(CHAT):c.1061C>T (p.Thr354Met)
HGVS:
  • NC_000010.11:g.49627735C>T
  • NG_011797.1:g.23641C>T
  • NM_001142929.1:c.707C>T
  • NM_001142933.1:c.815C>T
  • NM_001142934.1:c.707C>T
  • NM_020549.4:c.1061C>T
  • NM_020984.3:c.707C>T
  • NM_020985.3:c.707C>T
  • NM_020986.3:c.707C>T
  • NP_001136401.1:p.Thr236Met
  • NP_001136405.1:p.Thr272Met
  • NP_001136406.1:p.Thr236Met
  • NP_065574.3:p.Thr354Met
  • NP_066264.3:p.Thr236Met
  • NP_066265.3:p.Thr236Met
  • NP_066266.3:p.Thr236Met
  • NC_000010.10:g.50835781C>T
Protein change:
T236M
Links:
dbSNP: rs769234940
NCBI 1000 Genomes Browser:
rs769234940
Molecular consequence:
  • NM_001142929.1:c.707C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001142933.1:c.815C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001142934.1:c.707C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020549.4:c.1061C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020984.3:c.707C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020985.3:c.707C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020986.3:c.707C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial infantile myasthenia (CMS6)
Synonyms:
Congenital myasthenic syndrome with episodic apnea; Myasthenic syndrome congenital associated with episodic apnea; Myasthenic syndrome, presynaptic, congenital, associated with episodic apnea; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009689; MedGen: C0393929; Orphanet: 590; OMIM: 254210

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000758067Invitaecriteria provided, single submitter
Uncertain significance
(Aug 23, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Clinical variability of CMS-EA (congenital myasthenic syndrome with episodic apnea) due to identical CHAT mutations in two infants.

Barisic N, Müller JS, Paucic-Kirincic E, Gazdik M, Lah-Tomulic K, Pertl A, Sertic J, Zurak N, Lochmüller H, Abicht A.

Eur J Paediatr Neurol. 2005;9(1):7-12. Epub 2004 Dec 13.

PubMed [citation]
PMID:
15701560

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000758067.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces threonine with methionine at codon 354 of the CHAT protein (p.Thr354Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs769234940, ExAC 0.001%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with congenital myasthenic syndrome with episodic apnea (PMID: 15701560). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease.. ClinVar contains an entry for this variant (Variation ID: 523528). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5

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

Last Updated: Oct 8, 2021

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