Congenital myasthenic syndrome 21

Summary

Congenital myasthenic syndrome 21 (MONDO:0014983) is a disease caused by SLC18A3 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: SLC18A3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 21
Mondo ID	MONDO:0014983
OMIM	617239
DOID	DOID:0110672
UMLS	C4310654
MedGen	934621
GARD	0016212
Is cancer (heuristic)	no

Also known as: CMS21 · congenital myasthenic syndrome caused by mutation in SLC18A3 · congenital myasthenic syndrome type 21 · myasthenic syndrome, congenital, 21, presynaptic · SLC18A3 congenital myasthenic syndrome

Data availability: 21 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › congenital myasthenic syndrome › presynaptic congenital myasthenic syndrome › congenital myasthenic syndrome 21

Related subtypes (9): congenital myasthenic syndrome 6, congenital myasthenic syndrome 8, congenital myasthenic syndrome 7, congenital myasthenic syndrome 18, congenital myasthenic syndrome 19, congenital myasthenic syndrome 20, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

21 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 4 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
372160	NM_003055.3(SLC18A3):c.1192G>C (p.Asp398His)	CHAT	Likely pathogenic	criteria provided, single submitter
1582049	NM_003055.3(SLC18A3):c.41C>T (p.Ala14Val)	CHAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2907396	NM_003055.3(SLC18A3):c.1116C>A (p.Cys372Ter)	CHAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451787	NM_003055.3(SLC18A3):c.599T>A (p.Ile200Asn)	CHAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732977	NM_003055.3(SLC18A3):c.85C>T (p.Arg29Trp)	SLC18A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029501	NM_003055.3(SLC18A3):c.1093G>C (p.Ala365Pro)	CHAT	Uncertain significance	criteria provided, single submitter
1032110	NM_003055.3(SLC18A3):c.151A>G (p.Met51Val)	CHAT	Uncertain significance	criteria provided, single submitter
1032111	NM_003055.3(SLC18A3):c.88C>T (p.Arg30Trp)	CHAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1382334	NM_003055.3(SLC18A3):c.781G>C (p.Ala261Pro)	CHAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1394695	NM_003055.3(SLC18A3):c.183C>G (p.Ile61Met)	CHAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1413308	NM_003055.3(SLC18A3):c.646G>T (p.Val216Leu)	CHAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1923830	NM_003055.3(SLC18A3):c.1510G>T (p.Val504Leu)	CHAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065921	NM_003055.3(SLC18A3):c.539C>G (p.Ala180Gly)	CHAT	Uncertain significance	criteria provided, single submitter
3163236	NM_003055.3(SLC18A3):c.680T>G (p.Val227Gly)	CHAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
372159	NM_003055.3(SLC18A3):c.557G>C (p.Gly186Ala)	CHAT	Uncertain significance	criteria provided, single submitter
3897007	NM_003055.3(SLC18A3):c.1234C>A (p.Arg412Ser)	CHAT	Uncertain significance	criteria provided, single submitter
4080061	NM_003055.3(SLC18A3):c.229G>A (p.Val77Met)	CHAT	Uncertain significance	criteria provided, single submitter
4080062	NM_003055.3(SLC18A3):c.242C>T (p.Thr81Ile)	CHAT	Uncertain significance	criteria provided, single submitter
4080063	NM_003055.3(SLC18A3):c.295G>T (p.Ala99Ser)	CHAT	Uncertain significance	criteria provided, single submitter
4080064	NM_003055.3(SLC18A3):c.153G>A (p.Met51Ile)	CHAT	Uncertain significance	criteria provided, single submitter
802572	NM_003055.3(SLC18A3):c.1559C>A (p.Ala520Glu)	CHAT	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC18A3	Strong	Autosomal recessive	congenital myasthenic syndrome 21	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC18A3	Orphanet:98914	Presynaptic congenital myasthenic syndromes
SLC18A3	Orphanet:994	Fetal akinesia deformation sequence
CHAT	Orphanet:98914	Presynaptic congenital myasthenic syndromes

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC18A3	HGNC:10936	ENSG00000187714	Q16572	Vesicular acetylcholine transporter	gencc,clinvar
CHAT	HGNC:1912	ENSG00000070748	P28329	Choline O-acetyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC18A3	Vesicular acetylcholine transporter	Electrogenic antiporter that exchanges one cholinergic neurotransmitter, acetylcholine or choline, with two intravesicular protons across the membrane of synaptic vesicles.
CHAT	Choline O-acetyltransferase	Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	38.9×	0.051
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC18A3	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
CHAT	Enzyme (other)	yes	2.3.1.6	Carn_acyl_trans, CAT-like_dom_sf, Cho/carn_acyl_trans_1_2

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
putamen	2
endometrium epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC18A3	60	tissue_specific	yes	primordial germ cell in gonad, endometrium epithelium, putamen
CHAT	68	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, putamen

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHAT	1,743
SLC18A3	1,568

Intra-cohort edges

A	B	Sources
CHAT	SLC18A3	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC18A3	Q16572	11
CHAT	P28329	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Acetylcholine Neurotransmitter Release Cycle	2	671.8×	8e-06	SLC18A3, CHAT
Synthesis of PC	1	203.9×	0.010	CHAT
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.023	SLC18A3
Clathrin-mediated endocytosis	1	42.6×	0.023	SLC18A3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neurotransmitter transport	2	421.3×	5e-05	SLC18A3, CHAT
acetylcholine uptake	1	4213.0×	7e-04	SLC18A3
positive regulation of neuromuscular junction development	1	4213.0×	7e-04	SLC18A3
acetylcholine biosynthetic process	1	2808.7×	7e-04	CHAT
positive regulation of acetylcholine secretion, neurotransmission	1	2808.7×	7e-04	SLC18A3
serotonin uptake	1	766.0×	0.002	SLC18A3
phosphatidylcholine biosynthetic process	1	401.2×	0.004	CHAT
positive regulation of long-term synaptic potentiation	1	337.0×	0.004	SLC18A3
neuromuscular synaptic transmission	1	300.9×	0.004	CHAT
chemical synaptic transmission	1	38.6×	0.026	SLC18A3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHAT	1	3
SLC18A3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COENZYME_A	3	CHAT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SLC18A3	17	Binding:17
CHAT	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHAT	2.3.1.6	choline O-acetyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
COENZYME_A	3	CHAT

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	CHAT
C	Druggable family + PDB, no drug	1	SLC18A3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC18A3	17	CHAT

Clinical trials & evidence

Clinical trials

Clinical trials: 0.