Congenital myasthenic syndrome 20

Summary

Congenital myasthenic syndrome 20 (MONDO:0014939) is a disease caused by SLC5A7 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: SLC5A7 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 502

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 20
Mondo ID	MONDO:0014939
OMIM	617143
DOID	DOID:0110661
UMLS	C4310694
MedGen	934661
GARD	0016202
Is cancer (heuristic)	no

Also known as: CMS20 · congenital myasthenic syndrome caused by mutation in SLC5A7 · congenital myasthenic syndrome type 20 · myasthenic syndrome, congenital, 20, presynaptic · SLC5A7 congenital myasthenic syndrome

Data availability: 502 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 20

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 21, 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

502 retrieved; paginated sample, class counts are floors:

275 uncertain significance, 185 likely benign, 16 conflicting classifications of pathogenicity, 9 likely pathogenic, 7 pathogenic, 5 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
38790	NM_003060.4(SLC22A5):c.254_264dup (p.Ile89fs)	SLC22A5	Pathogenic	criteria provided, multiple submitters, no conflicts
1426671	NM_021815.5(SLC5A7):c.364dup (p.Tyr122fs)	SLC5A7	Pathogenic	criteria provided, single submitter
265765	NM_021815.5(SLC5A7):c.143A>G (p.Asp48Gly)	SLC5A7	Pathogenic	no assertion criteria provided
3752933	NM_021815.5(SLC5A7):c.719G>A (p.Trp240Ter)	SLC5A7	Pathogenic	criteria provided, single submitter
3756992	NM_021815.5(SLC5A7):c.134del (p.Gly45fs)	SLC5A7	Pathogenic	criteria provided, single submitter
4784269	NM_021815.5(SLC5A7):c.836del (p.Phe279fs)	SLC5A7	Pathogenic	criteria provided, single submitter
4788433	NM_021815.5(SLC5A7):c.101dup (p.Ser34fs)	SLC5A7	Pathogenic	criteria provided, single submitter
1009672	NM_021815.5(SLC5A7):c.292+1G>A	SLC5A7	Likely pathogenic	criteria provided, single submitter
1027324	NM_021815.5(SLC5A7):c.895+1G>C	SLC5A7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1415144	NM_021815.5(SLC5A7):c.179-2A>G	SLC5A7	Likely pathogenic	criteria provided, single submitter
265763	NM_021815.5(SLC5A7):c.1082G>A (p.Arg361Gln)	SLC5A7	Likely pathogenic	criteria provided, single submitter
265764	NM_021815.5(SLC5A7):c.123_126del (p.Ala41_Ile42insTer)	SLC5A7	Likely pathogenic	criteria provided, single submitter
2687476	NM_021815.5(SLC5A7):c.178+2T>C	SLC5A7	Likely pathogenic	no assertion criteria provided
2687766	NM_021815.5(SLC5A7):c.1207T>C (p.Tyr403His)	SLC5A7	Likely pathogenic	no assertion criteria provided
2687767	NM_021815.5(SLC5A7):c.1349G>A (p.Gly450Glu)	SLC5A7	Likely pathogenic	no assertion criteria provided
4293912	NM_021815.5(SLC5A7):c.881T>C (p.Ile294Thr)	SLC5A7	Likely pathogenic	criteria provided, single submitter
1042814	NM_021815.5(SLC5A7):c.1177A>G (p.Thr393Ala)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1476505	NM_021815.5(SLC5A7):c.81G>A (p.Trp27Ter)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1596627	NM_021815.5(SLC5A7):c.742-5C>T	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1810255	NM_021815.5(SLC5A7):c.320G>A (p.Arg107His)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2542724	NM_021815.5(SLC5A7):c.1480A>G (p.Ile494Val)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440281	NM_021815.5(SLC5A7):c.1306G>A (p.Val436Met)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464174	NM_021815.5(SLC5A7):c.46C>T (p.Leu16Phe)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
532814	NM_021815.5(SLC5A7):c.1643G>A (p.Arg548Gln)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
532824	NM_021815.5(SLC5A7):c.1237G>A (p.Val413Ile)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
549706	NM_021815.5(SLC5A7):c.1549G>A (p.Val517Ile)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
572646	NM_021815.5(SLC5A7):c.385C>T (p.Leu129Phe)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
580407	NM_021815.5(SLC5A7):c.1246G>A (p.Val416Ile)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
648681	NM_021815.5(SLC5A7):c.1478G>T (p.Cys493Phe)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
650165	NM_021815.5(SLC5A7):c.973C>A (p.Gln325Lys)	SLC5A7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
SLC5A7	Strong	Autosomal recessive	congenital myasthenic syndrome 20	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC5A7	Orphanet:139589	Distal hereditary motor neuropathy type 7
SLC5A7	Orphanet:98914	Presynaptic congenital myasthenic syndromes
SLC22A5	Orphanet:158	Systemic primary carnitine deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC5A7	HGNC:14025	ENSG00000115665	Q9GZV3	High affinity choline transporter 1	gencc,clinvar
SLC22A5	HGNC:10969	ENSG00000197375	O76082	Organic cation/carnitine transporter 2	clinvar
SULT1C2	HGNC:11456	ENSG00000198203	O00338	Sulfotransferase 1C2	clinvar
CCDC138	HGNC:26531	ENSG00000163006	Q96M89	Coiled-coil domain-containing protein 138	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC5A7	High affinity choline transporter 1	High-affinity Na(+)-coupled choline transmembrane symporter.
SLC22A5	Organic cation/carnitine transporter 2	Sodium-ion dependent, high affinity carnitine transporter.
SULT1C2	Sulfotransferase 1C2	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) to catalyze the sulfate conjugation of phenolic compounds.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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	2	38.9×	0.002
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC5A7	Transporter	yes		Na/solute_symporter, Na/Glc_symporter_sf, Choline_transporter
SLC22A5	Transporter	yes		Orgcat_transp/SVOP, MFS_sugar_transport-like, Sugar_transporter_CS
SULT1C2	Other/Unknown	no		Sulfotransferase_dom, P-loop_NTPase
CCDC138	Other/Unknown	no		CCDC138, CCDC138_C, CCDC138_CC

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
pancreatic ductal cell	1
primordial germ cell in gonad	1
gastrocnemius	1
mucosa of transverse colon	1
muscle of leg	1
nephron tubule	1
pylorus	1
renal medulla	1
sperm	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC5A7	101	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell, primordial germ cell in gonad
SLC22A5	235	ubiquitous	marker	gastrocnemius, mucosa of transverse colon, muscle of leg
SULT1C2	191	broad	marker	pylorus, nephron tubule, renal medulla
CCDC138	178	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, sperm, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC5A7	1,536
SLC22A5	1,492
CCDC138	829
SULT1C2	620

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC5A7	Q9GZV3	12
SLC22A5	O76082	3
SULT1C2	O00338	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CCDC138	Q96M89	73.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SLC transporter disorders	2	135.9×	0.001	SLC5A7, SLC22A5
R-HSA-425366	2	120.8×	0.001	SLC5A7, SLC22A5
Disorders of transmembrane transporters	2	92.8×	0.001	SLC5A7, SLC22A5
Defective SLC5A7 in the neurotransmitter release cycle causes distal hereditary motor neuronopathy 7A (HMN7A)	1	3806.7×	0.001	SLC5A7
Defective transport by SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A)	1	3806.7×	0.001	SLC5A7
Defective SLC22A5 causes systemic primary carnitine deficiency (CDSP)	1	1903.3×	0.002	SLC22A5
SLC-mediated transmembrane transport	2	39.5×	0.003	SLC5A7, SLC22A5
SLC-mediated bile acid transport	1	543.8×	0.005	SLC5A7
Carnitine shuttle	1	253.8×	0.008	SLC22A5
SLC-mediated transport of organic cations	1	253.8×	0.008	SLC22A5
R-HSA-549132	1	253.8×	0.008	SLC22A5
Acetylcholine Neurotransmitter Release Cycle	1	223.9×	0.008	SLC5A7
Transport of small molecules	2	16.8×	0.008	SLC5A7, SLC22A5
Cytosolic sulfonation of small molecules	1	173.0×	0.009	SULT1C2
Neurotransmitter release cycle	1	146.4×	0.010	SLC5A7
Phase II - Conjugation of compounds	1	92.8×	0.015	SULT1C2
Disease	2	8.7×	0.022	SLC5A7, SLC22A5
Fatty acid metabolism	1	43.8×	0.026	SLC22A5
Biological oxidations	1	43.3×	0.026	SULT1C2
Metabolism	2	7.7×	0.026	SLC22A5, SULT1C2
Transmission across Chemical Synapses	1	25.4×	0.043	SLC5A7
Neuronal System	1	14.8×	0.069	SLC5A7
Metabolism of lipids	1	10.5×	0.092	SLC22A5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of intestinal epithelial structure maintenance	1	2808.7×	0.002	SLC22A5
sodium-dependent organic cation transport	1	2808.7×	0.002	SLC22A5
(R)-carnitine transport	1	2808.7×	0.002	SLC22A5
acetylcholine biosynthetic process	1	1872.4×	0.002	SLC5A7
(R)-carnitine transmembrane transport	1	1872.4×	0.002	SLC22A5
carnitine transport	1	1404.3×	0.003	SLC22A5
quaternary ammonium group transport	1	1123.5×	0.003	SLC22A5
response to symbiotic bacterium	1	936.2×	0.003	SLC22A5
carnitine transmembrane transport	1	936.2×	0.003	SLC22A5
amine metabolic process	1	802.5×	0.003	SULT1C2
choline transport	1	510.7×	0.004	SLC5A7
xenobiotic detoxification by transmembrane export across the plasma membrane	1	374.5×	0.005	SLC22A5
sulfation	1	351.1×	0.005	SULT1C2
synaptic transmission, cholinergic	1	267.5×	0.006	SLC5A7
response to tumor necrosis factor	1	208.1×	0.007	SLC22A5
neuromuscular synaptic transmission	1	200.6×	0.007	SLC5A7
response to type II interferon	1	175.5×	0.007	SLC22A5
neurotransmitter transport	1	140.4×	0.009	SLC5A7
sodium ion transport	1	90.6×	0.013	SLC22A5
transport across blood-brain barrier	1	59.8×	0.018	SLC22A5
transmembrane transport	1	56.2×	0.019	SLC5A7
in utero embryonic development	1	24.0×	0.041	SLC5A7

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC5A7	1	3
SLC22A5	0	0
SULT1C2	0	0
CCDC138	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHOLINE CHLORIDE	3	SLC5A7

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC22A5	97	Functional:79, ADMET:18
SLC5A7	34	Binding:24, Functional:10
SULT1C2	1	ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
CHOLINE CHLORIDE	3	SLC5A7

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	SLC5A7
C	Druggable family + PDB, no drug	1	SLC22A5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SULT1C2, CCDC138

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC22A5	97	—
SULT1C2	1	—
CCDC138	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.