Congenital myasthenic syndrome 12

Summary

Congenital myasthenic syndrome 12 (MONDO:0012518) is a disease caused by GFPT1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: GFPT1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 541

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 12
Mondo ID	MONDO:0012518
OMIM	610542
DOID	DOID:0110660
NCIT	C168997
UMLS	C3552335
MedGen	765249
GARD	0018451
Is cancer (heuristic)	no

Also known as: CMS12 · congenital myasthenic syndrome type 12 · congenital myasthenic syndromes with glycosylation defect caused by mutation in GFPT1 · GFPT1 congenital myasthenic syndromes with glycosylation defect · myasthenia, congenital, 12, with tubular aggregates · myasthenic syndrome, congenital, 12 · myasthenic syndrome, congenital, type 12

Data availability: 541 ClinVar variants · 6 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital myasthenic syndrome with tubular aggregates › congenital myasthenic syndrome 12

Related subtypes (2): congenital myasthenic syndrome 13, congenital myasthenic syndrome 14

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

541 retrieved; paginated sample, class counts are floors:

236 uncertain significance, 193 likely benign, 44 benign, 29 pathogenic, 18 conflicting classifications of pathogenicity, 14 likely pathogenic, 5 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067128	NM_001244710.2(GFPT1):c.44C>T (p.Thr15Met)	GFPT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069341	NC_000002.11:g.(?69553299)(69614213_?)del	GFPT1	Pathogenic	criteria provided, single submitter
1070025	NM_001244710.2(GFPT1):c.931C>T (p.Arg311Ter)	GFPT1	Pathogenic	criteria provided, single submitter
1070689	NM_001244710.2(GFPT1):c.1290dup (p.Arg431fs)	GFPT1	Pathogenic	criteria provided, single submitter
1073321	NM_001244710.2(GFPT1):c.332G>A (p.Arg111His)	GFPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073758	NM_001244710.2(GFPT1):c.686dup (p.Ala229_Arg230insTer)	GFPT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1252034	NM_001244710.2(GFPT1):c.686-1G>A	GFPT1	Pathogenic	no assertion criteria provided
1455957	NM_001244710.2(GFPT1):c.769_772del (p.Ser257fs)	GFPT1	Pathogenic	criteria provided, single submitter
1927249	NM_001244710.2(GFPT1):c.728_729del (p.Gln243fs)	GFPT1	Pathogenic	criteria provided, single submitter
1949433	NM_001244710.2(GFPT1):c.1851T>G (p.Tyr617Ter)	GFPT1	Pathogenic	criteria provided, single submitter
2002398	NM_001244710.2(GFPT1):c.1687C>T (p.Arg563Ter)	GFPT1	Pathogenic	criteria provided, single submitter
2424021	NC_000002.11:g.(?69583608)(69583709_?)del	GFPT1	Pathogenic	criteria provided, single submitter
2424022	NC_000002.11:g.(?69573016)(69575486_?)del	GFPT1	Pathogenic	criteria provided, single submitter
2719778	NM_001244710.2(GFPT1):c.1291C>T (p.Arg431Ter)	GFPT1	Pathogenic	criteria provided, single submitter
29735	NM_001244710.2(GFPT1):c.331C>T (p.Arg111Cys)	GFPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29736	NM_001244710.2(GFPT1):c.224dup (p.Gln76fs)	GFPT1	Pathogenic	no assertion criteria provided
29737	NM_001244710.2(GFPT1):c.719G>A (p.Trp240Ter)	GFPT1	Pathogenic	criteria provided, single submitter
29738	NM_001244710.2(GFPT1):c.1096G>T (p.Asp366Tyr)	GFPT1	Pathogenic	no assertion criteria provided
29740	NM_001244710.2(GFPT1):c.621del (p.Leu207_Leu208insTer)	GFPT1	Pathogenic	no assertion criteria provided
3010186	NM_001244710.2(GFPT1):c.741dup (p.Lys248fs)	GFPT1	Pathogenic	criteria provided, single submitter
3668591	NM_001244710.2(GFPT1):c.762C>A (p.Cys254Ter)	GFPT1	Pathogenic	criteria provided, single submitter
444502	NM_001244710.2(GFPT1):c.738_739del (p.Gly247fs)	GFPT1	Pathogenic	criteria provided, multiple submitters, no conflicts
4768063	NM_001244710.2(GFPT1):c.714dup (p.Arg239fs)	GFPT1	Pathogenic	criteria provided, single submitter
4804077	NM_001244710.2(GFPT1):c.2T>G (p.Met1Arg)	GFPT1	Pathogenic	criteria provided, single submitter
540353	NM_001244710.2(GFPT1):c.686-2A>G	GFPT1	Pathogenic	criteria provided, multiple submitters, no conflicts
570975	NM_001244710.2(GFPT1):c.982C>T (p.Gln328Ter)	GFPT1	Pathogenic	criteria provided, single submitter
583230	NM_001244710.2(GFPT1):c.197_201del (p.Val66fs)	GFPT1	Pathogenic	criteria provided, single submitter
631477	NM_001244710.2(GFPT1):c.41G>T (p.Arg14Leu)	GFPT1	Pathogenic	no assertion criteria provided
631478	NM_001244710.2(GFPT1):c.452C>A (p.Thr151Lys)	GFPT1	Pathogenic	no assertion criteria provided
836225	NM_001244710.2(GFPT1):c.89_90del (p.Leu30fs)	GFPT1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 13 · 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
GFPT1	Definitive	Autosomal recessive	congenital myasthenic syndrome 12	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GFPT1	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GFPT1	HGNC:4241	ENSG00000198380	Q06210	Glutamine–fructose-6-phosphate aminotransferase [isomerizing] 1	gencc,clinvar
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
FAT1	HGNC:3595	ENSG00000083857	Q14517	Protocadherin Fat 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GFPT1	Glutamine–fructose-6-phosphate aminotransferase [isomerizing] 1	Rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP) that catalyzes the formation of glucosamine-6-phosphate from fructose-6-phosphate and glutamine, thereby controlling the flux of glucose into this pathway.
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
FAT1	Protocadherin Fat 1	Plays an essential role for cellular polarization, directed cell migration and modulating cell-cell contact.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Ion channel	1	37.2×	0.080
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GFPT1	Enzyme (other)	yes	2.6.1.16	SIS_dom, GFAT, GATase_2_dom
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
FAT1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic mucosa	1
mucosa of sigmoid colon	1
secondary oocyte	1
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1
choroid plexus epithelium	1
metanephric glomerulus	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GFPT1	287	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, secondary oocyte
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
FAT1	288	ubiquitous	marker	choroid plexus epithelium, tibia, metanephric glomerulus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GFPT1	2,798
FAT1	2,446
RYR1	2,177

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GFPT1	Q06210	16
RYR1	P21817	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FAT1	Q14517

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 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
Defective GFPT1 causes CMSTA1	1	5710.0×	0.002	GFPT1
Synthesis of UDP-N-acetyl-glucosamine	1	713.8×	0.006	GFPT1
XBP1(S) activates chaperone genes	1	107.7×	0.022	GFPT1
Ion homeostasis	1	102.0×	0.022	RYR1
Stimuli-sensing channels	1	68.0×	0.026	RYR1
Cardiac conduction	1	54.4×	0.027	RYR1
Ion channel transport	1	48.0×	0.027	RYR1
Muscle contraction	1	38.6×	0.029	RYR1
Transport of small molecules	1	12.6×	0.078	RYR1

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
establishment of epithelial cell apical/basal polarity involved in camera-type eye morphogenesis	1	5617.3×	0.006	FAT1
UDP-N-acetylglucosamine metabolic process	1	936.2×	0.009	GFPT1
response to caffeine	1	802.5×	0.009	RYR1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	561.7×	0.009	RYR1
UDP-N-acetylglucosamine biosynthetic process	1	510.7×	0.009	GFPT1
cellular response to caffeine	1	510.7×	0.009	RYR1
ossification involved in bone maturation	1	468.1×	0.009	RYR1
fructose 6-phosphate metabolic process	1	374.5×	0.009	GFPT1
energy reserve metabolic process	1	351.1×	0.009	GFPT1
positive regulation of vascular associated smooth muscle cell migration	1	330.4×	0.009	FAT1
epithelial cell morphogenesis	1	312.1×	0.009	FAT1
cellular response to angiotensin	1	312.1×	0.009	FAT1
striated muscle contraction	1	280.9×	0.009	RYR1
skeletal muscle fiber development	1	181.2×	0.013	RYR1
skin development	1	147.8×	0.015	RYR1
cell-cell adhesion mediated by cadherin	1	137.0×	0.015	FAT1
regulation of cytosolic calcium ion concentration	1	127.7×	0.015	RYR1
lens development in camera-type eye	1	124.8×	0.015	FAT1
release of sequestered calcium ion into cytosol	1	114.6×	0.015	RYR1
outflow tract morphogenesis	1	102.1×	0.016	RYR1
protein N-linked glycosylation	1	87.8×	0.018	GFPT1
protein homotetramerization	1	79.1×	0.018	RYR1
circadian regulation of gene expression	1	78.0×	0.018	GFPT1
muscle contraction	1	69.3×	0.020	RYR1
cellular response to calcium ion	1	66.9×	0.020	RYR1
calcium ion transport	1	60.4×	0.021	RYR1
homophilic cell-cell adhesion	1	46.8×	0.025	FAT1
anatomical structure morphogenesis	1	46.4×	0.025	FAT1
actin filament organization	1	39.6×	0.029	FAT1
response to hypoxia	1	31.9×	0.034	RYR1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GFPT1	0	0
RYR1	0	0
FAT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RYR1	16	Binding:13, Functional:3
GFPT1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GFPT1	2.6.1.16	glutamine-fructose-6-phosphate transaminase (isomerizing)

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

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	2	GFPT1, RYR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FAT1

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)
GFPT1	8	—
RYR1	16	—
FAT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.