CHAT

Chr 10AR

choline O-acetyltransferase

Also known as: CHOACTASE, CMS1A, CMS1A2, CMS6

NCBI Gene: 1103 ENSG00000070748 UniProt: P28329 OMIM: 118490

This gene encodes choline acetyltransferase, the enzyme that catalyzes acetylcholine biosynthesis in cholinergic neurons. Mutations cause congenital myasthenic syndrome type 6 with episodic apnea through autosomal recessive inheritance. The pathogenic mechanism involves presynaptic dysfunction due to impaired acetylcholine synthesis at the neuromuscular junction.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, Mechanism

This gene encodes an enzyme which catalyzes the biosynthesis of the neurotransmitter acetylcholine. This gene product is a characteristic feature of cholinergic neurons, and changes in these neurons may explain some of the symptoms of Alzheimer's disease. Polymorphisms in this gene have been associated with Alzheimer's disease and mild cognitive impairment. Mutations in this gene are associated with congenital myasthenic syndrome associated with episodic apnea. Multiple transcript variants encoding different isoforms have been found for this gene, and some of these variants have been shown to encode more than one isoform. [provided by RefSeq, May 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.881 OMIM phenotype

Clinical Summary— CHAT

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Gene-Disease Validity (ClinGen)

congenital myasthenic syndrome 6 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

118 unique Pathogenic / Likely Pathogenic· 511 VUS of 1387 total submissions

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CHAT

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.000

Z-score 2.11

OE 0.62 (0.44–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.30Z-score

OE missense 0.96 (0.89–1.04)

414 obs / 431.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.44–0.88)

0≤0.351.4

Missense OE?0.96 (0.89–1.04)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 22 / 35.6Missense obs/exp: 414 / 431.3Syn Z: -1.44

This gene — mechanism propensity

0.6939th %ile

GOF

0.5464th %ile

LOF

0.3066th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1387 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41

Likely Pathogenic77

VUS511

Likely Benign614

Benign93

Conflicting51

Pathogenic

Likely Pathogenic

511

VUS

614

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	31	5	5	0	41
Likely Pathogenic	49	26	2	0	77
VUS	14	473	16	8	511
Likely Benign	1	26	192	395	614
Benign	0	10	66	17	93
Conflicting	—				51
Total	95	540	281	420	1,387

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

60 pathogenic / likely-pathogenic (of 94) ClinVar copy-number / structural variants overlap CHAT — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →