autosomal dominant limb-girdle muscular dystrophy type 1F

Summary

autosomal dominant limb-girdle muscular dystrophy type 1F (MONDO:0012034) is a disease caused by TNPO3 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TNPO3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 632
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		64	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant limb-girdle muscular dystrophy type 1F
Mondo ID	MONDO:0012034
MeSH	C564242
OMIM	608423
Orphanet	55595
DOID	DOID:0110304
SNOMED CT	719989007
UMLS	C1842062
MedGen	333983
GARD	0012530
Is cancer (heuristic)	no

Also known as: LGMD1F · limb-girdle muscular dystrophy type 1F · muscular dystrophy, limb-girdle, autosomal dominant 2 · muscular dystrophy, limb-girdle, type 1F

Data availability: 632 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › muscular dystrophy, limb-girdle, autosomal dominant › autosomal dominant limb-girdle muscular dystrophy type 1F

Related subtypes (7): autosomal dominant limb-girdle muscular dystrophy type 1G, myofibrillar myopathy 3, autosomal dominant limb-girdle muscular dystrophy type 1H, autosomal dominant limb-girdle muscular dystrophy type 1E (DES), autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6), Emery-Dreifuss muscular dystrophy 2, autosomal dominant, muscular dystrophy, limb-girdle, autosomal dominant 4

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

600 retrieved; paginated sample, class counts are floors:

290 uncertain significance, 240 likely benign, 37 conflicting classifications of pathogenicity, 23 benign, 4 benign/likely benign, 3 pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323699	NM_012470.4(TNPO3):c.163C>T (p.Gln55Ter)	TNPO3	Pathogenic	criteria provided, single submitter
135660	NM_012470.4(TNPO3):c.2771del (p.Ter924CysextTer?)	TNPO3	Pathogenic	no assertion criteria provided
135661	NM_012470.4(TNPO3):c.2453G>C (p.Arg818Pro)	TNPO3	Pathogenic	no assertion criteria provided
2434191	NM_012470.4(TNPO3):c.1423dup (p.Thr475fs)	TNPO3	Likely pathogenic	criteria provided, single submitter
2585348	NM_012470.4(TNPO3):c.2430+1G>A	TNPO3	Likely pathogenic	criteria provided, single submitter
591000	NM_012470.4(TNPO3):c.2767del (p.Arg923fs)	TNPO3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
499031	NM_012470.4(TNPO3):c.30C>T (p.Leu10=)	LOC129999289	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043244	NM_012470.4(TNPO3):c.1841G>A (p.Arg614His)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194964	NM_012470.4(TNPO3):c.2326A>G (p.Ile776Val)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
199129	NM_012470.4(TNPO3):c.1179T>C (p.Thr393=)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2162860	NM_012470.4(TNPO3):c.831G>C (p.Glu277Asp)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2201355	NM_012470.4(TNPO3):c.2413A>G (p.Thr805Ala)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2437152	NM_012470.4(TNPO3):c.1105A>G (p.Ile369Val)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
260267	NM_012470.4(TNPO3):c.582T>C (p.Asp194=)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282446	NM_012470.4(TNPO3):c.2741C>T (p.Ala914Val)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283011	NM_012470.4(TNPO3):c.696+8A>G	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283060	NM_012470.4(TNPO3):c.2070T>C (p.Asn690=)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283108	NM_012470.4(TNPO3):c.275C>T (p.Thr92Ile)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283447	NM_012470.4(TNPO3):c.2625C>T (p.Ser875=)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283491	NM_012470.4(TNPO3):c.2274-5A>G	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285330	NM_012470.4(TNPO3):c.857G>A (p.Arg286His)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285709	NM_012470.4(TNPO3):c.2079C>T (p.His693=)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286140	NM_012470.4(TNPO3):c.2599-6A>G	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286472	NM_012470.4(TNPO3):c.1810A>G (p.Ile604Val)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288188	NM_012470.4(TNPO3):c.1851G>T (p.Val617=)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289358	NM_012470.4(TNPO3):c.804A>G (p.Gln268=)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289758	NM_012470.4(TNPO3):c.906A>G (p.Leu302=)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290303	NM_012470.4(TNPO3):c.234C>T (p.Leu78=)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290312	NM_012470.4(TNPO3):c.318G>A (p.Thr106=)	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
389221	NM_012470.4(TNPO3):c.873-3C>T	TNPO3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
TNPO3	Strong	Autosomal dominant	autosomal dominant limb-girdle muscular dystrophy type 1F	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNPO3	Orphanet:186	Primary biliary cholangitis
TNPO3	Orphanet:55595	TNP03-related limb-girdle muscular dystrophy D2

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNPO3	HGNC:17103	ENSG00000064419	Q9Y5L0	Transportin-3	gencc,clinvar
CALU	HGNC:1458	ENSG00000128595	O43852	Calumenin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNPO3	Transportin-3	Importin, which transports target proteins into the nucleus.
CALU	Calumenin	Involved in regulation of vitamin K-dependent carboxylation of multiple N-terminal glutamate residues.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNPO3	Other/Unknown	no		ARM-like, Exportin-1/Importin-b-like, ARM-type_fold
CALU	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tendon of biceps brachii	2
medial globus pallidus	1
secondary oocyte	1
smooth muscle tissue	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNPO3	299	ubiquitous	marker	secondary oocyte, tendon of biceps brachii, medial globus pallidus
CALU	303	ubiquitous	marker	stromal cell of endometrium, smooth muscle tissue, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNPO3	2,970
CALU	2,013

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNPO3	Q9Y5L0	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CALU	O43852	79.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 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
Response to elevated platelet cytosolic Ca2+	1	163.1×	0.018	CALU
Platelet activation, signaling and aggregation	1	105.7×	0.018	CALU
Post-translational protein phosphorylation	1	100.2×	0.018	CALU
Platelet degranulation	1	87.8×	0.018	CALU
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.018	CALU
Hemostasis	1	36.0×	0.037	CALU
Post-translational protein modification	1	19.2×	0.060	CALU
Metabolism of proteins	1	12.4×	0.081	CALU

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
protein import into nucleus	1	144.0×	0.007	TNPO3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNPO3	0	0
CALU	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TNPO3	1	Binding:1
CALU	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	TNPO3, CALU

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNPO3	1	—
CALU	1	—

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