autosomal recessive limb-girdle muscular dystrophy type 2T

Summary

autosomal recessive limb-girdle muscular dystrophy type 2T (MONDO:0014142) is a disease caused by GMPPB (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GMPPB (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 334
• Phenotypes (HPO): 25
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000467	Neck muscle weakness	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0003327	Axial muscle weakness	Occasional (5-29%)
HP:0003388	Easy fatigability	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003403	EMG: decremental response of compound muscle action potential to repetitive nerve stimulation	Occasional (5-29%)
HP:0003546	Exercise intolerance	Occasional (5-29%)
HP:0006698	Dilatation of the ventricular cavity	Occasional (5-29%)
HP:0007340	Lower limb muscle weakness	Occasional (5-29%)
HP:0008959	Distal upper limb muscle weakness	Occasional (5-29%)
HP:0008997	Proximal muscle weakness in upper limbs	Occasional (5-29%)
HP:0009053	Distal lower limb muscle weakness	Occasional (5-29%)
HP:0030192	Fatigable weakness of bulbar muscles	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive limb-girdle muscular dystrophy type 2T
Mondo ID	MONDO:0014142
OMIM	615352
Orphanet	363623
DOID	DOID:0110294
UMLS	C4518000
MedGen	1377325
GARD	0012544
Is cancer (heuristic)	no

Also known as: autosomal recessive limb-girdle muscular dystrophy caused by mutation in GMPPB · GMPPB autosomal recessive limb-girdle muscular dystrophy · LGMD-GMPPB related · LGMD2T · limb-girdle muscular dystrophy type 2T · MDDGC14 · muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14

Data availability: 334 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 muscular dystrophy › muscular dystrophy-dystroglycanopathy › muscular dystrophy-dystroglycanopathy, type C › autosomal recessive limb-girdle muscular dystrophy type 2T

Related subtypes (8): autosomal recessive limb-girdle muscular dystrophy type 2K, autosomal recessive limb-girdle muscular dystrophy type 2M, autosomal recessive limb-girdle muscular dystrophy type 2O, autosomal recessive limb-girdle muscular dystrophy type 2N, autosomal recessive limb-girdle muscular dystrophy type 2P, autosomal recessive limb-girdle muscular dystrophy type 2U, limb-girdle muscular dystrophy due to POMK deficiency, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8

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

334 retrieved; paginated sample, class counts are floors:

137 likely benign, 126 uncertain significance, 20 pathogenic, 17 conflicting classifications of pathogenicity, 14 likely pathogenic, 12 pathogenic/likely pathogenic, 5 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072060	NM_021971.4(GMPPB):c.294dup (p.Glu99Ter)	GMPPB	Pathogenic	criteria provided, single submitter
1508556	NM_021971.4(GMPPB):c.1039_1042dup (p.Ser348Ter)	GMPPB	Pathogenic	criteria provided, single submitter
1948644	NM_021971.4(GMPPB):c.1051_1054dup (p.Ser352Ter)	GMPPB	Pathogenic	criteria provided, single submitter
2001208	NM_021971.4(GMPPB):c.225del (p.Ser76fs)	GMPPB	Pathogenic	criteria provided, single submitter
2070938	NM_021971.4(GMPPB):c.972dup (p.Val325fs)	GMPPB	Pathogenic	criteria provided, single submitter
2125713	NM_021971.4(GMPPB):c.951G>A (p.Trp317Ter)	GMPPB	Pathogenic	criteria provided, single submitter
2151975	NM_021971.4(GMPPB):c.854_855del (p.Cys285fs)	GMPPB	Pathogenic	criteria provided, single submitter
225925	NM_021971.4(GMPPB):c.859C>T (p.Arg287Trp)	GMPPB	Pathogenic	criteria provided, multiple submitters, no conflicts
2936436	NM_021971.4(GMPPB):c.132_141del (p.Gly45fs)	GMPPB	Pathogenic	criteria provided, single submitter
2953265	NM_021971.4(GMPPB):c.618dup (p.Leu207fs)	GMPPB	Pathogenic	criteria provided, single submitter
3750006	NM_021971.4(GMPPB):c.444del (p.Cys149fs)	GMPPB	Pathogenic	criteria provided, single submitter
474016	NM_021971.4(GMPPB):c.365_366dup (p.Phe123fs)	GMPPB	Pathogenic	criteria provided, single submitter
474017	NM_021971.4(GMPPB):c.458_459del (p.Thr153fs)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4783624	NM_021971.4(GMPPB):c.797G>A (p.Cys266Tyr)	GMPPB	Pathogenic	criteria provided, single submitter
560362	NM_021971.4(GMPPB):c.358A>G (p.Met120Val)	GMPPB	Pathogenic	criteria provided, single submitter
570106	NM_021971.4(GMPPB):c.402+1G>A	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
571713	NM_021971.4(GMPPB):c.790C>T (p.Gln264Ter)	GMPPB	Pathogenic	criteria provided, single submitter
575991	NM_021971.4(GMPPB):c.656T>C (p.Ile219Thr)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60540	NM_021971.4(GMPPB):c.1000G>A (p.Asp334Asn)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60542	NM_021971.4(GMPPB):c.64C>T (p.Pro22Ser)	GMPPB	Pathogenic	no assertion criteria provided
60543	NM_021971.4(GMPPB):c.553C>T (p.Arg185Cys)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60544	NM_021971.4(GMPPB):c.95C>T (p.Pro32Leu)	GMPPB	Pathogenic	criteria provided, multiple submitters, no conflicts
60545	NM_021971.4(GMPPB):c.860G>A (p.Arg287Gln)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60546	NM_021971.4(GMPPB):c.79G>C (p.Asp27His)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60547	NM_021971.4(GMPPB):c.988G>A (p.Val330Ile)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620253	NM_021971.4(GMPPB):c.490C>T (p.Gln164Ter)	GMPPB	Pathogenic	criteria provided, multiple submitters, no conflicts
638638	NM_021971.4(GMPPB):c.458C>T (p.Thr153Ile)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
640954	NM_021971.4(GMPPB):c.640+1G>A	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
647358	NM_021971.4(GMPPB):c.109C>T (p.Gln37Ter)	GMPPB	Pathogenic	criteria provided, single submitter
663873	NM_021971.4(GMPPB):c.271_283del (p.Ala91fs)	GMPPB	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · 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
GMPPB	Definitive	Autosomal recessive	muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GMPPB	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect
GMPPB	Orphanet:363623	GMPPB-related limb-girdle muscular dystrophy R19
GMPPB	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
GMPPB	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
GMPPB	Orphanet:588	Muscle-eye-brain disease

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
GMPPB	HGNC:22932	ENSG00000173540	Q9Y5P6	Mannose-1-phosphate guanylyltransferase catalytic subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GMPPB	Mannose-1-phosphate guanylyltransferase catalytic subunit beta	Catalytic subunit of the GMPPA-GMPPB mannose-1-phosphate guanylyltransferase complex.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GMPPB	Enzyme (other)	yes	2.7.7.13	NTP_transferase_dom, Hexapep_transf_CS, Nucleotide-diphossugar_trans

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
adenohypophysis	1
body of pancreas	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GMPPB	172	ubiquitous	marker	body of pancreas, adenohypophysis, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GMPPB	2,559

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GMPPB	Q9Y5P6	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
Synthesis of GDP-mannose	1	1903.3×	5e-04	GMPPB

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
obsolete GDP-mannose biosynthetic process from mannose	1	5617.3×	4e-04	GMPPB
GDP-mannose biosynthetic process	1	2808.7×	4e-04	GMPPB
GDP-mannose metabolic process	1	2808.7×	4e-04	GMPPB

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
GMPPB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GMPPB	2.7.7.13	mannose-1-phosphate guanylyltransferase

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	1	GMPPB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
GMPPB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments