Congenital myasthenic syndrome 13

Summary

Congenital myasthenic syndrome 13 (MONDO:0013883) is a disease caused by DPAGT1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: DPAGT1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 275

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 13
Mondo ID	MONDO:0013883
OMIM	614750
DOID	DOID:0110676
UMLS	C3553645
MedGen	766559
GARD	0018452
Is cancer (heuristic)	no

Also known as: CMS13 · CMSTA2 · congenital myasthenic syndrome type 13 · congenital myasthenic syndromes with glycosylation defect caused by mutation in DPAGT1 · DPAGT1 congenital myasthenic syndromes with glycosylation defect · myasthenic syndrome, congenital, 13 · myasthenic syndrome, congenital, 13, with tubular aggregates · myasthenic syndrome, congenital, type 13

Data availability: 275 ClinVar variants · 3 GenCC gene-disease records.

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 13

Related subtypes (2): congenital myasthenic syndrome 12, 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

275 retrieved; paginated sample, class counts are floors:

116 likely benign, 99 uncertain significance, 25 conflicting classifications of pathogenicity, 14 pathogenic, 11 likely pathogenic, 5 pathogenic/likely pathogenic, 4 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
652390	NC_000011.9:g.(?118967698)(119170501_?)del	CBL	Pathogenic	criteria provided, single submitter
1180632	NM_001382.4(DPAGT1):c.902G>A (p.Arg301His)	DPAGT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1373663	NM_001382.4(DPAGT1):c.1139C>T (p.Thr380Ile)	DPAGT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451203	NM_001382.4(DPAGT1):c.762_765del (p.Cys255fs)	DPAGT1	Pathogenic	criteria provided, single submitter
2927002	NM_001382.4(DPAGT1):c.732C>A (p.Tyr244Ter)	DPAGT1	Pathogenic	criteria provided, single submitter
36919	NM_001382.4(DPAGT1):c.324G>C (p.Met108Ile)	DPAGT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36920	NM_001382.4(DPAGT1):c.699dup (p.Thr234fs)	DPAGT1	Pathogenic	criteria provided, single submitter
36921	NM_001382.4(DPAGT1):c.358C>A (p.Leu120Met)	DPAGT1	Pathogenic	no assertion criteria provided
36922	NM_001382.4(DPAGT1):c.791T>G (p.Val264Gly)	DPAGT1	Pathogenic	no assertion criteria provided
3752613	NM_001382.4(DPAGT1):c.980_981del (p.Ser327fs)	DPAGT1	Pathogenic	criteria provided, single submitter
381709	NM_001382.4(DPAGT1):c.1A>C (p.Met1Leu)	DPAGT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4785074	NM_001382.4(DPAGT1):c.172C>T (p.Gln58Ter)	DPAGT1	Pathogenic	criteria provided, single submitter
4786678	NM_001382.4(DPAGT1):c.737C>A (p.Ser246Ter)	DPAGT1	Pathogenic	criteria provided, single submitter
521720	NM_001382.4(DPAGT1):c.380_395dup (p.Ser133fs)	DPAGT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
565496	NM_001382.4(DPAGT1):c.360G>C (p.Leu120=)	DPAGT1	Pathogenic	criteria provided, single submitter
640003	NM_001382.4(DPAGT1):c.398C>G (p.Ser133Ter)	DPAGT1	Pathogenic	criteria provided, single submitter
1460468	NM_001382.4(DPAGT1):c.6G>A (p.Trp2Ter)	LOC126861360	Pathogenic	criteria provided, single submitter
2944371	NM_001382.4(DPAGT1):c.79del (p.Thr27fs)	LOC126861360	Pathogenic	criteria provided, single submitter
567578	NM_001382.4(DPAGT1):c.26dup (p.Met9fs)	LOC126861360	Pathogenic	criteria provided, single submitter
1299537	NM_001382.4(DPAGT1):c.1097T>C (p.Leu366Ser)	DPAGT1	Likely pathogenic	criteria provided, single submitter
1333389	NM_001382.4(DPAGT1):c.457A>T (p.Lys153Ter)	DPAGT1	Likely pathogenic	criteria provided, single submitter
1480366	NM_001382.4(DPAGT1):c.644-1G>T	DPAGT1	Likely pathogenic	criteria provided, single submitter
1685304	NM_001382.4(DPAGT1):c.643+1G>A	DPAGT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2499560	NM_001382.4(DPAGT1):c.742G>A (p.Val248Met)	DPAGT1	Likely pathogenic	criteria provided, single submitter
2954181	NM_001382.4(DPAGT1):c.1005+1G>A	DPAGT1	Likely pathogenic	criteria provided, single submitter
3382969	NM_001382.4(DPAGT1):c.728+1del	DPAGT1	Likely pathogenic	criteria provided, single submitter
36918	NM_001382.4(DPAGT1):c.349G>A (p.Val117Ile)	DPAGT1	Likely pathogenic	criteria provided, single submitter
4786262	NM_001382.4(DPAGT1):c.282+1G>A	DPAGT1	Likely pathogenic	criteria provided, single submitter
4845787	NM_001382.4(DPAGT1):c.698dup (p.Thr234fs)	DPAGT1	Likely pathogenic	criteria provided, single submitter
65469	NM_001382.4(DPAGT1):c.341C>G (p.Ala114Gly)	DPAGT1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 7 · 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
DPAGT1	Definitive	Autosomal recessive	DPAGT1-congenital disorder of glycosylation	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DPAGT1	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect
DPAGT1	Orphanet:86309	DPAGT1-CDG
CBL	Orphanet:363972	Noonan syndrome-like disorder with juvenile myelomonocytic leukemia
CBL	Orphanet:648	Noonan syndrome
CBL	Orphanet:86834	Juvenile myelomonocytic leukemia
CBL	Orphanet:98850	Aggressive systemic mastocytosis
GFPT1	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect

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
DPAGT1	HGNC:2995	ENSG00000172269	Q9H3H5	UDP-N-acetylglucosamine–dolichyl-phosphate N-acetylglucosaminephosphotransferase	gencc,clinvar
CBL	HGNC:1541	ENSG00000110395	P22681	E3 ubiquitin-protein ligase CBL	clinvar
NLRX1	HGNC:29890	ENSG00000160703	Q86UT6	NLR family member X1	clinvar
GFPT1	HGNC:4241	ENSG00000198380	Q06210	Glutamine–fructose-6-phosphate aminotransferase [isomerizing] 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DPAGT1	UDP-N-acetylglucosamine–dolichyl-phosphate N-acetylglucosaminephosphotransferase	UDP-N-acetylglucosamine–dolichyl-phosphate N-acetylglucosaminephosphotransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
CBL	E3 ubiquitin-protein ligase CBL	E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors.
NLRX1	NLR family member X1	Participates in antiviral signaling.
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.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · 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
Enzyme (other)	2	6.0×	0.112
Transcription factor	1	2.1×	0.605
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DPAGT1	Enzyme (other)	yes	2.7.8.15	Glycosyl_transferase_4, GPT, DPAGT1_ins
CBL	Transcription factor	no	2.3.2.27	Znf_RING, Adaptor_Cbl_N_hlx, UBA-like_sf
NLRX1	Other/Unknown	no		Leu-rich_rpt, NACHT_NTPase, P-loop_NTPase
GFPT1	Enzyme (other)	yes	2.6.1.16	SIS_dom, GFAT, GATase_2_dom

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
mucosa of transverse colon	1
right adrenal gland	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
trigeminal ganglion	1
cervix squamous epithelium	1
esophagus mucosa	1
lower esophagus mucosa	1
colonic mucosa	1
mucosa of sigmoid colon	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DPAGT1	271	ubiquitous	marker	mucosa of transverse colon, body of pancreas, right adrenal gland
CBL	271	ubiquitous	marker	primordial germ cell in gonad, trigeminal ganglion, male germ line stem cell (sensu Vertebrata) in testis
NLRX1	262	ubiquitous	yes	lower esophagus mucosa, cervix squamous epithelium, esophagus mucosa
GFPT1	287	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CBL	4,575
GFPT1	2,798
DPAGT1	1,928
NLRX1	1,310

Intra-cohort edges

A	B	Sources
DPAGT1	GFPT1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CBL	P22681	33
GFPT1	Q06210	16
DPAGT1	Q9H3H5	8
NLRX1	Q86UT6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 59. Enrichment computed across 4 evidence-associated genes (4 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 4 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	2855.0×	0.017	GFPT1
Defective DPAGT1 causes CDG-1j, CMSTA2	1	1427.5×	0.017	DPAGT1
Signaling by EGFRvIII in Cancer	1	571.0×	0.017	CBL
Signaling by Ligand-Responsive EGFR Variants in Cancer	1	475.8×	0.017	CBL
FLT3 signaling by CBL mutants	1	407.9×	0.017	CBL
Synthesis of UDP-N-acetyl-glucosamine	1	356.9×	0.017	GFPT1
Interleukin-6 family signaling	1	356.9×	0.017	CBL
PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1	1	317.2×	0.017	CBL
Signaling by EGFR in Cancer	1	285.5×	0.017	CBL
Signaling by FGFR3	1	285.5×	0.017	CBL
FLT3 signaling in disease	1	285.5×	0.017	CBL
Signaling by FGFR4	1	259.6×	0.017	CBL
Listeria monocytogenes entry into host cells	1	259.6×	0.017	CBL
Interleukin-6 signaling	1	237.9×	0.017	CBL
Signaling by FGFR1	1	203.9×	0.017	CBL
InlB-mediated entry of Listeria monocytogenes into host cell	1	190.3×	0.017	CBL
Spry regulation of FGF signaling	1	178.4×	0.017	CBL
Constitutive Signaling by EGFRvIII	1	178.4×	0.017	CBL
Negative regulation of FLT3	1	178.4×	0.017	CBL
Regulation of NF-kappa B signaling	1	158.6×	0.018	NLRX1
Regulation of KIT signaling	1	150.3×	0.018	CBL
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	142.8×	0.018	CBL
Signaling by PTK6	1	135.9×	0.018	CBL
Signaling by Non-Receptor Tyrosine Kinases	1	135.9×	0.018	CBL
Negative regulation of MET activity	1	129.8×	0.018	CBL
Regulation of signaling by CBL	1	124.1×	0.018	CBL
Negative regulation of FGFR3 signaling	1	109.8×	0.018	CBL
Negative regulation of FGFR4 signaling	1	102.0×	0.018	CBL
Signaling by FGFR2	1	102.0×	0.018	CBL
Negative regulation of FGFR1 signaling	1	92.1×	0.018	CBL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein N-linked glycosylation	2	131.7×	0.004	DPAGT1, GFPT1
regulation of platelet-derived growth factor receptor-alpha signaling pathway	1	1404.3×	0.014	CBL
regulation of Rap protein signal transduction	1	1053.2×	0.014	CBL
UDP-N-acetylglucosamine metabolic process	1	702.2×	0.016	GFPT1
negative regulation of RIG-I signaling pathway	1	526.6×	0.016	NLRX1
ubiquitin-dependent endocytosis	1	468.1×	0.016	CBL
UDP-N-acetylglucosamine biosynthetic process	1	383.0×	0.016	GFPT1
negative regulation of macrophage cytokine production	1	300.9×	0.016	NLRX1
fructose 6-phosphate metabolic process	1	280.9×	0.016	GFPT1
energy reserve metabolic process	1	263.3×	0.016	GFPT1
negative regulation of interferon-beta production	1	263.3×	0.016	NLRX1
dolichol-linked oligosaccharide biosynthetic process	1	210.7×	0.017	DPAGT1
positive regulation of receptor-mediated endocytosis	1	200.6×	0.017	CBL
negative regulation of epidermal growth factor receptor signaling pathway	1	191.5×	0.017	CBL
cellular response to platelet-derived growth factor stimulus	1	162.0×	0.017	CBL
mast cell degranulation	1	156.0×	0.017	CBL
response to gamma radiation	1	145.3×	0.017	CBL
negative regulation of T cell activation	1	131.7×	0.017	CBL
negative regulation of innate immune response	1	127.7×	0.017	NLRX1
positive regulation of epidermal growth factor receptor signaling pathway	1	123.9×	0.017	CBL
response to testosterone	1	117.0×	0.017	CBL
response to starvation	1	117.0×	0.017	CBL
cellular response to nerve growth factor stimulus	1	117.0×	0.017	CBL
symbiont entry into host cell	1	100.3×	0.019	CBL
negative regulation of T cell receptor signaling pathway	1	91.6×	0.019	CBL
negative regulation of interleukin-6 production	1	87.8×	0.019	NLRX1
protein monoubiquitination	1	86.0×	0.019	CBL
response to activity	1	81.0×	0.020	CBL
protein K63-linked ubiquitination	1	66.9×	0.023	CBL
circadian regulation of gene expression	1	58.5×	0.025	GFPT1

Therapeutics

Drug target analysis

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

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
DPAGT1	0	0
CBL	0	0
NLRX1	0	0
GFPT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
GFPT1	8	Binding:8
DPAGT1	7	Binding:7
CBL	4	Binding:2, Toxicity:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DPAGT1	2.7.8.15	UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase
CBL	2.3.2.27	RING-type E3 ubiquitin transferase
GFPT1	2.6.1.16	glutamine-fructose-6-phosphate transaminase (isomerizing)

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

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	DPAGT1, GFPT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CBL, NLRX1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DPAGT1	7	—
CBL	4	—
NLRX1	0	—
GFPT1	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.