congenital myasthenic syndrome 1A

Summary

congenital myasthenic syndrome 1A (MONDO:0011088) is a disease caused by CHRNA1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CHRNA1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 1A
Mondo ID	MONDO:0011088
OMIM	601462
DOID	DOID:0110663
UMLS	C2931107
MedGen	419336
GARD	0015330
Is cancer (heuristic)	no

Also known as: CHRNA1 congenital myasthenic syndrome · Cms IIa · CMS1A · congenital myasthenic syndrome caused by mutation in CHRNA1 · congenital myasthenic syndrome type 1A · myasthenic syndrome, congenital, 1A, slow-channel · myasthenic syndrome, congenital, type IIa

Data availability: 28 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › postsynaptic congenital myasthenic syndrome › congenital myasthenic syndrome 1A

Related subtypes (13): congenital myasthenic syndrome 10, congenital myasthenic syndrome 16, congenital myasthenic syndrome 8, congenital myasthenic syndrome 17, congenital myasthenic syndrome 2A, congenital myasthenic syndrome 2C, congenital myasthenic syndrome 3A, congenital myasthenic syndrome 3B, congenital myasthenic syndrome 3C, congenital myasthenic syndrome 9, congenital myasthenic syndrome 11, congenital myasthenic syndrome 19, congenital myasthenic syndrome 4

Subtypes (1): myasthenic syndrome, congenital, 1B, fast-channel

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

28 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 5 pathogenic, 4 likely pathogenic, 4 benign, 3 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
243031	NM_000080.4(CHRNE):c.1327del	C17orf107	Pathogenic	criteria provided, multiple submitters, no conflicts
18376	NM_000079.4(CHRNA1):c.711C>G (p.Asn237Lys)	CHRNA1	Pathogenic	no assertion criteria provided
18378	NM_000079.4(CHRNA1):c.821C>T (p.Thr274Ile)	CHRNA1	Pathogenic	no assertion criteria provided
18379	NM_000079.4(CHRNA1):c.517G>A (p.Gly173Ser)	CHRNA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18380	NM_000079.4(CHRNA1):c.866G>T (p.Ser289Ile)	CHRNA1	Pathogenic	no assertion criteria provided
18387	NM_000079.4(CHRNA1):c.1314C>G (p.Cys438Trp)	CHRNA1	Pathogenic	no assertion criteria provided
418733	NM_000079.4(CHRNA1):c.518dup (p.Ser174fs)	CHRNA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1177411	NM_000079.4(CHRNA1):c.254T>C (p.Leu85Pro)	CHRNA1	Likely pathogenic	criteria provided, single submitter
3255616	NM_000079.4(CHRNA1):c.44-1G>T	CHRNA1	Likely pathogenic	criteria provided, single submitter
3362606	NM_000079.4(CHRNA1):c.440_444del (p.Ser146_Tyr147insTer)	CHRNA1	Likely pathogenic	criteria provided, single submitter
4845289	NM_000079.4(CHRNA1):c.425C>T (p.Ala142Val)	CHRNA1	Likely pathogenic	criteria provided, single submitter
1366831	NM_000079.4(CHRNA1):c.935C>A (p.Thr312Asn)	CHRNA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18381	NM_000079.4(CHRNA1):c.805G>T (p.Val269Phe)	CHRNA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
430309	NM_000079.4(CHRNA1):c.778G>T (p.Gly260Trp)	CHRNA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1252011	NM_000079.4(CHRNA1):c.685C>T (p.Arg229Cys)	CHRNA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1687566	NM_000079.4(CHRNA1):c.902C>G (p.Thr301Ser)	CHRNA1	Uncertain significance	criteria provided, single submitter
1802258	NM_000079.4(CHRNA1):c.191A>C (p.Asp64Ala)	CHRNA1	Uncertain significance	criteria provided, single submitter
1804381	NM_000079.4(CHRNA1):c.1189G>A (p.Glu397Lys)	CHRNA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
18377	NM_000079.4(CHRNA1):c.526G>A (p.Val176Met)	CHRNA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1999935	NM_000079.4(CHRNA1):c.746C>A (p.Thr249Asn)	CHRNA1	Uncertain significance	criteria provided, single submitter
2584890	NM_000079.4(CHRNA1):c.1003G>T (p.Val335Phe)	CHRNA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4845290	NM_000079.4(CHRNA1):c.182T>C (p.Ile61Thr)	CHRNA1	Uncertain significance	criteria provided, single submitter
534525	NM_000079.4(CHRNA1):c.320G>A (p.Arg107His)	CHRNA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
930934	NM_000079.4(CHRNA1):c.766C>A (p.Pro256Thr)	CHRNA1	Uncertain significance	criteria provided, single submitter
257235	NM_000079.4(CHRNA1):c.190-5del	CHRNA1	Benign	criteria provided, multiple submitters, no conflicts
257237	NM_000079.4(CHRNA1):c.235-385C>T	CHRNA1	Benign	criteria provided, multiple submitters, no conflicts
679132	NM_000079.4(CHRNA1):c.1003-53A>G	CHRNA1	Benign	criteria provided, multiple submitters, no conflicts
680121	NM_000079.4(CHRNA1):c.43+59G>T	CHRNA1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
CHRNA1	Strong	Autosomal dominant	congenital myasthenic syndrome 1A	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHRNA1	Orphanet:33108	Lethal multiple pterygium syndrome
CHRNA1	Orphanet:98913	Postsynaptic congenital myasthenic syndrome

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
CHRNA1	HGNC:1955	ENSG00000138435	P02708	Acetylcholine receptor subunit alpha	gencc,clinvar
C17orf107	HGNC:37238	ENSG00000205710	Q6ZR85	Uncharacterized protein C17orf107	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHRNA1	Acetylcholine receptor subunit alpha	Upon acetylcholine binding, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHRNA1	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
C17orf107	Other/Unknown	no		C17orf107

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
gastrocnemius	1
gluteal muscle	1
muscle of leg	1
adenohypophysis	1
pituitary gland	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHRNA1	149	broad	marker	gastrocnemius, gluteal muscle, muscle of leg
C17orf107	131	broad	yes	adenohypophysis, pituitary gland, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHRNA1	1,058
C17orf107	110

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHRNA1	P02708	15

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C17orf107	Q6ZR85	58.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Highly calcium permeable nicotinic acetylcholine receptors	1	1268.9×	0.002	CHRNA1
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	1038.2×	0.002	CHRNA1
Presynaptic nicotinic acetylcholine receptors	1	951.7×	0.002	CHRNA1
Acetylcholine binding and downstream events	1	815.7×	0.002	CHRNA1
Postsynaptic nicotinic acetylcholine receptors	1	815.7×	0.002	CHRNA1
Neurotransmitter receptors and postsynaptic signal transmission	1	100.2×	0.013	CHRNA1
Transmission across Chemical Synapses	1	76.1×	0.015	CHRNA1
Neuronal System	1	44.3×	0.023	CHRNA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skeletal muscle tissue growth	1	2808.7×	0.003	CHRNA1
musculoskeletal movement	1	2808.7×	0.003	CHRNA1
synaptic transmission, cholinergic	1	802.5×	0.003	CHRNA1
muscle cell cellular homeostasis	1	648.1×	0.003	CHRNA1
acetylcholine receptor signaling pathway	1	624.1×	0.003	CHRNA1
neuromuscular synaptic transmission	1	601.9×	0.003	CHRNA1
neuromuscular junction development	1	526.6×	0.003	CHRNA1
neuromuscular process	1	526.6×	0.003	CHRNA1
skeletal muscle contraction	1	510.7×	0.003	CHRNA1
membrane depolarization	1	510.7×	0.003	CHRNA1
neuronal action potential	1	481.5×	0.003	CHRNA1
neuron cellular homeostasis	1	455.5×	0.003	CHRNA1
presynaptic modulation of chemical synaptic transmission	1	455.5×	0.003	CHRNA1
response to nicotine	1	421.3×	0.003	CHRNA1
regulation of membrane potential	1	230.8×	0.005	CHRNA1
monoatomic ion transmembrane transport	1	208.1×	0.005	CHRNA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CHRNA1	VARENICLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHRNA1	12	4
C17orf107	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARENICLINE	4	CHRNA1
NICOTINE	4	CHRNA1
TROPISETRON	4	CHRNA1
BUPROPION	4	CHRNA1
MECAMYLAMINE	4	CHRNA1
DEXMECAMYLAMINE	3	CHRNA1
CYTISINICLINE	3	CHRNA1
RADAFAXINE	2	CHRNA1
GTS-21	2	CHRNA1
ALTINICLINE	2	CHRNA1
MOLIBRESIB	2	CHRNA1
TC-2216	1	CHRNA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CHRNA1	157	Binding:107, Functional:47, ADMET:2, Toxicity:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CHRNA1	157

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

12 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)
VARENICLINE	4	CHRNA1
NICOTINE	4	CHRNA1
TROPISETRON	4	CHRNA1
BUPROPION	4	CHRNA1
MECAMYLAMINE	4	CHRNA1
DEXMECAMYLAMINE	3	CHRNA1
CYTISINICLINE	3	CHRNA1
RADAFAXINE	2	CHRNA1
GTS-21	2	CHRNA1
ALTINICLINE	2	CHRNA1
MOLIBRESIB	2	CHRNA1
TC-2216	1	CHRNA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CHRNA1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	C17orf107

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)
C17orf107	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.