Congenital myasthenic syndrome 5

Summary

Congenital myasthenic syndrome 5 (MONDO:0011281) is a disease caused by COLQ (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: COLQ (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 524
• Phenotypes (HPO): 54

Clinical features

Signs & symptoms

Clinical features (HPO)

54 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0003324	Generalized muscle weakness	Very frequent (80-99%)
HP:0003403	EMG: decremental response of compound muscle action potential to repetitive nerve stimulation	Very frequent (80-99%)
HP:0003701	Proximal muscle weakness	Very frequent (80-99%)
HP:0000467	Neck muscle weakness	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000597	Ophthalmoparesis	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001488	Bilateral ptosis	Frequent (30-79%)
HP:0001612	Weak cry	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002033	Poor suck	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002515	Waddling gait	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003398	Abnormal synaptic transmission at the neuromuscular junction	Frequent (30-79%)
HP:0003436	Prolonged miniature endplate currents	Frequent (30-79%)
HP:0003443	Decreased size of nerve terminals	Frequent (30-79%)
HP:0003691	Scapular winging	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0012379	Abnormal enzyme/coenzyme activity	Frequent (30-79%)
HP:0030203	Unfavorable response of muscle weakness to acetylcholine esterase inhibitors	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0002643	Neonatal respiratory distress	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002783	Recurrent lower respiratory tract infections	Occasional (5-29%)
HP:0002791	Hypoventilation	Occasional (5-29%)
HP:0002815	Abnormality of the knee	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0003327	Axial muscle weakness	Occasional (5-29%)
HP:0003388	Easy fatigability	Occasional (5-29%)
HP:0003803	Type 1 muscle fiber predominance	Occasional (5-29%)
HP:0005216	Impaired mastication	Occasional (5-29%)
HP:0007941	Limited extraocular movements	Occasional (5-29%)
HP:0010535	Sleep apnea	Occasional (5-29%)
HP:0030211	Slow pupillary light response	Occasional (5-29%)
HP:0000207	Triangular mouth	Very rare (<1-4%)
HP:0000303	Mandibular prognathia	Very rare (<1-4%)
HP:0001667	Right ventricular hypertrophy	Very rare (<1-4%)
HP:0001762	Talipes equinovarus	Very rare (<1-4%)
HP:0001999	Abnormal facial shape	Very rare (<1-4%)
HP:0002092	Pulmonary arterial hypertension	Very rare (<1-4%)
HP:0002359	Frequent falls	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 5
Mondo ID	MONDO:0011281
MeSH	C566415
OMIM	603034
Orphanet	98915
DOID	DOID:0110667
NCIT	C129304
UMLS	C1864233
MedGen	400481
GARD	0018210
Is cancer (heuristic)	no

Also known as: Cms Ic · CMS5 · COLQ congenital myasthenic syndrome · congenital myasthenic syndrome 5 · congenital myasthenic syndrome caused by mutation in COLQ · congenital myasthenic syndrome type 5 · EAD · Engel congenital myasthenic syndrome · myasthenic syndrome, congenital, 5 · myasthenic syndrome, congenital, type 5

Data availability: 524 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › congenital myasthenic syndrome › congenital myasthenic syndrome 5

Related subtypes (7): congenital myasthenic syndrome with tubular aggregates, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 15, postsynaptic congenital myasthenic syndrome, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, myasthenic syndrome, congenital, 22, presynaptic congenital myasthenic syndrome

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

524 retrieved; paginated sample, class counts are floors:

204 uncertain significance, 163 likely benign, 53 pathogenic, 38 likely pathogenic, 24 benign, 17 conflicting classifications of pathogenicity, 17 pathogenic/likely pathogenic, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069916	NM_005677.4(COLQ):c.361G>T (p.Glu121Ter)	COLQ	Pathogenic	criteria provided, single submitter
1069918	NM_005677.4(COLQ):c.798del (p.Gly267fs)	COLQ	Pathogenic	criteria provided, single submitter
1070410	NM_005677.4(COLQ):c.1111C>T (p.Gln371Ter)	COLQ	Pathogenic	criteria provided, single submitter
1071042	NM_005677.4(COLQ):c.377del (p.Gly126fs)	COLQ	Pathogenic	criteria provided, multiple submitters, no conflicts
1299712	NM_005677.4:c.(814+1_815-1)_(954+1_955-1)del	COLQ	Pathogenic	no assertion criteria provided
1322155	NM_005677.4(COLQ):c.955-2A>T	COLQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1356041	NM_005677.4(COLQ):c.1005_1008del (p.Asn335fs)	COLQ	Pathogenic	criteria provided, single submitter
1383050	NM_005677.4(COLQ):c.700G>T (p.Gly234Ter)	COLQ	Pathogenic	criteria provided, multiple submitters, no conflicts
1416795	NM_005677.4(COLQ):c.1195+2T>C	COLQ	Pathogenic	criteria provided, single submitter
1448843	NM_005677.4(COLQ):c.893del (p.Asn298fs)	COLQ	Pathogenic	criteria provided, multiple submitters, no conflicts
1679827	NM_005677.4(COLQ):c.1061G>A (p.Trp354Ter)	COLQ	Pathogenic	criteria provided, single submitter
1685664	NM_005677.4(COLQ):c.1195+2T>G	COLQ	Pathogenic	criteria provided, single submitter
1801824	NM_005677.4(COLQ):c.1026C>G (p.Asp342Glu)	COLQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2017269	NM_005677.4(COLQ):c.109dup (p.Leu37fs)	COLQ	Pathogenic	criteria provided, single submitter
2018622	NM_005677.4(COLQ):c.682G>T (p.Gly228Ter)	COLQ	Pathogenic	criteria provided, single submitter
2203311	NM_005677.4(COLQ):c.176C>A (p.Pro59Gln)	COLQ	Pathogenic	criteria provided, single submitter
2421993	NM_005677.4(COLQ):c.175C>T (p.Pro59Ser)	COLQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2435808	NM_005677.4(COLQ):c.241_242dup (p.Asn81fs)	COLQ	Pathogenic	criteria provided, multiple submitters, no conflicts
2444318	NM_005677.4(COLQ):c.109del (p.Leu37fs)	COLQ	Pathogenic	criteria provided, single submitter
2576521	NM_005677.4(COLQ):c.827_843del (p.Met276fs)	COLQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2579192	GRCh38/hg38 3p25.1(chr3:15488109-15489735)x0	COLQ	Pathogenic	criteria provided, single submitter
2671287	NM_005677.4(COLQ):c.955-2A>C	COLQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680856	NM_005677.4(COLQ):c.631C>T (p.Gln211Ter)	COLQ	Pathogenic	criteria provided, multiple submitters, no conflicts
2680857	NM_005677.4(COLQ):c.992_998del (p.Leu331fs)	COLQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680858	NM_005677.4(COLQ):c.706C>T (p.Arg236Ter)	COLQ	Pathogenic	criteria provided, single submitter
2716578	NM_005677.4(COLQ):c.118del (p.Leu40fs)	COLQ	Pathogenic	criteria provided, single submitter
280125	NM_005677.4(COLQ):c.679C>T (p.Arg227Ter)	COLQ	Pathogenic	criteria provided, multiple submitters, no conflicts
281421	NM_005677.4(COLQ):c.529-2A>G	COLQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2910166	NM_005677.4(COLQ):c.847G>T (p.Gly283Ter)	COLQ	Pathogenic	criteria provided, single submitter
3064097	NM_005677.4(COLQ):c.865G>T (p.Gly289Ter)	COLQ	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
COLQ	Strong	Autosomal recessive	congenital myasthenic syndrome 5	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COLQ	Orphanet:98915	Synaptic congenital myasthenic syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COLQ	HGNC:2226	ENSG00000206561	Q9Y215	Acetylcholinesterase collagenic tail peptide	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COLQ	Acetylcholinesterase collagenic tail peptide	Anchors the catalytic subunits of asymmetric AChE to the synaptic basal membrane, and is therefore involved in the down-regulation of colinergic synaptic transmission.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COLQ	Other/Unknown	no		Collagen, Myxo_disulph_rpt, Collagen_superfamily

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
hindlimb stylopod muscle	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COLQ	178	broad	marker	right uterine tube, hindlimb stylopod muscle, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COLQ	1,132

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COLQ	Q9Y215	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
acetylcholine catabolic process in synaptic cleft	1	8426.0×	5e-04	COLQ
negative regulation of synaptic transmission, cholinergic	1	5617.3×	5e-04	COLQ
skeletal muscle acetylcholine-gated channel clustering	1	1872.4×	7e-04	COLQ
establishment of protein localization to membrane	1	1872.4×	7e-04	COLQ
regulation of synaptic assembly at neuromuscular junction	1	1685.2×	7e-04	COLQ
protein localization to synapse	1	766.0×	0.001	COLQ

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COLQ	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	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	COLQ

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)
COLQ	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.