NM_020549.5(CHAT):c.1007T>C (p.Ile336Thr) AND Familial infantile myasthenia

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Mar 28, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000019067.32

Allele description [Variation Report for NM_020549.5(CHAT):c.1007T>C (p.Ile336Thr)]

NM_020549.5(CHAT):c.1007T>C (p.Ile336Thr)

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.1007T>C (p.Ile336Thr)

HGVS:

NC_000010.11:g.49627681T>C
NG_011797.1:g.23587T>C
NM_001142929.2:c.653T>C
NM_001142933.2:c.761T>C
NM_001142934.2:c.653T>C
NM_020549.5:c.1007T>CMANE SELECT
NM_020984.4:c.653T>C
NM_020985.4:c.653T>C
NM_020986.4:c.653T>C
NP_001136401.2:p.Ile218Thr
NP_001136405.2:p.Ile254Thr
NP_001136406.2:p.Ile218Thr
NP_065574.4:p.Ile336Thr
NP_066264.4:p.Ile218Thr
NP_066265.4:p.Ile218Thr
NP_066266.4:p.Ile218Thr
NC_000010.10:g.50835727T>C
P28329:p.Ile336Thr

Protein change:

I218T; ILE336THR

Links:

UniProtKB: P28329#VAR_038605; OMIM: 118490.0011; dbSNP: rs121912823

NCBI 1000 Genomes Browser:

rs121912823

Molecular consequence:

NM_001142929.2:c.653T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142933.2:c.761T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142934.2:c.653T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020549.5:c.1007T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020984.4:c.653T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020985.4:c.653T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020986.4:c.653T>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039354	OMIM	no assertion criteria provided	Pathogenic (May 1, 2003)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001450591	Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences	no assertion criteria provided	Pathogenic (Mar 3, 2016)	germline	clinical testing
SCV004294368	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 19, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12609506, 28492532
SCV005057483	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 28, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Iranian	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Congenital myasthenic syndrome with episodic apnea in patients homozygous for a CHAT missense mutation.

Kraner S, Laufenberg I, Strassburg HM, Sieb JP, Steinlein OK.

Arch Neurol. 2003 May;60(5):761-3.

PubMed [citation]

PMID:: 12756141

Congenital myasthenic syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase.

Schmidt C, Abicht A, Krampfl K, Voss W, Stucka R, Mildner G, Petrova S, Schara U, Mortier W, Bufler J, Huebner A, Lochmüller H.

Neuromuscul Disord. 2003 Mar;13(3):245-51.

PubMed [citation]

PMID:: 12609506

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000039354.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a consanguineous Turkish family in which 2 sibs had congenital myasthenic syndrome-6 (CMS6; 254210) with episodic apnea, Kraner et al. (2003) identified a homozygous 1187T-C transition in exon 7 of the CHAT gene, resulting in an ile336-to-thr (I336T) substitution. The unaffected parents were heterozygous for the mutation, which was absent in 164 control chromosomes.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences, SCV001450591.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Iranian	not provided	not provided	not provided	clinical testing	not provided

Description

The patient was a 27-year-old male with difficulty climbing stairs after exercise, facial weakness, difficulty chewing, mild ptosis muscle weakness mostly in upper extremities since childhood.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004294368.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. 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 CHAT protein function. ClinVar contains an entry for this variant (Variation ID: 17515). This missense change has been observed in individuals with congenital myasthenic syndrome (PMID: 12609506). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121912823, gnomAD 0.006%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 336 of the CHAT protein (p.Ile336Thr).

#	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

From Baylor Genetics, SCV005057483.1

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

#	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: Jun 17, 2024

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