Geleophysic dysplasia 3

Summary

Geleophysic dysplasia 3 (MONDO:0054722) is a disease caused by LTBP3 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: LTBP3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	geleophysic dysplasia 3
Mondo ID	MONDO:0054722
OMIM	617809
DOID	DOID:0111727
UMLS	C4540511
MedGen	1615724
GARD	0016255
Is cancer (heuristic)	no

Also known as: GPHYSD3

Data availability: 24 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 › skeletal dysplasia › acromelic dysplasia › geleophysic dysplasia › geleophysic dysplasia 3

Related subtypes (2): geleophysic dysplasia 1, geleophysic dysplasia 2

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

24 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 4 conflicting classifications of pathogenicity, 4 pathogenic, 3 benign/likely benign, 2 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1327506	NM_001130144.3(LTBP3):c.2017G>T (p.Gly673Cys)	LTBP3	Pathogenic	criteria provided, single submitter
3773667	NM_001130144.3(LTBP3):c.3646G>T (p.Glu1216Ter)	LTBP3	Pathogenic	criteria provided, single submitter
448912	NM_001130144.3(LTBP3):c.3912A>T (p.Ter1304Cys)	LTBP3	Pathogenic	criteria provided, single submitter
448913	NM_001130144.3(LTBP3):c.1846+5G>A	LTBP3	Pathogenic	no assertion criteria provided
1067470	NM_001130144.3(LTBP3):c.2893+1G>T	LTBP3	Likely pathogenic	criteria provided, single submitter
3600095	NM_001130144.3(LTBP3):c.1979-1G>A	LTBP3	Likely pathogenic	criteria provided, single submitter
1168659	NM_001130144.3(LTBP3):c.2458G>A (p.Asp820Asn)	LTBP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
403062	NM_001130144.3(LTBP3):c.76CTG[12] (p.Leu34_Leu35dup)	LTBP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464029	NM_001130144.3(LTBP3):c.76CTG[13] (p.Leu33_Leu35dup)	LTBP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
548546	NM_001130144.3(LTBP3):c.989C>T (p.Pro330Leu)	LTBP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3773666	NM_001130144.3(LTBP3):c.3036C>G (p.Asn1012Lys)	LOC121832793	Uncertain significance	criteria provided, single submitter
1377363	NM_001130144.3(LTBP3):c.3392C>T (p.Ala1131Val)	LOC130006027	Uncertain significance	criteria provided, multiple submitters, no conflicts
4293465	NM_001130144.3(LTBP3):c.3385+1G>C	LOC130006027	Uncertain significance	criteria provided, single submitter
1683537	NM_001130144.3(LTBP3):c.1942C>T (p.Arg648Cys)	LOC130006032	Uncertain significance	criteria provided, multiple submitters, no conflicts
1003708	NM_001130144.3(LTBP3):c.1072G>A (p.Glu358Lys)	LTBP3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1350463	NM_001130144.3(LTBP3):c.3438C>T (p.Gly1146=)	LTBP3	Uncertain significance	criteria provided, single submitter
1446821	NM_001130144.3(LTBP3):c.76CTG[6] (p.Leu32_Leu35del)	LTBP3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2202375	NM_001130144.3(LTBP3):c.1897A>C (p.Met633Leu)	LTBP3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4293519	NM_001130144.3(LTBP3):c.3673_3687dup (p.Val1229_Pro1230insSerGlyArgCysVal)	LTBP3	Uncertain significance	criteria provided, single submitter
448911	NM_001130144.3(LTBP3):c.2087C>G (p.Ser696Cys)	LTBP3	Uncertain significance	criteria provided, single submitter
1563314	NM_001130144.3(LTBP3):c.2107+13C>T	LTBP3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
532697	NM_001130144.3(LTBP3):c.76CTG[9] (p.Leu35del)	LTBP3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
697813	NM_001130144.3(LTBP3):c.1077C>T (p.Cys359=)	LTBP3	Benign	criteria provided, multiple submitters, no conflicts
772609	NM_001130144.3(LTBP3):c.3519A>G (p.Gln1173=)	LTBP3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · Orphanet: 6 · 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
LTBP2	Strong	Autosomal dominant	geleophysic dysplasia 3	20
LTBP3	Strong	Autosomal dominant	geleophysic dysplasia 3	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LTBP2	Orphanet:238763	Glaucoma secondary to spherophakia/ectopia lentis and megalocornea
LTBP2	Orphanet:3449	Weill-Marchesani syndrome
LTBP2	Orphanet:98976	Congenital glaucoma
LTBP3	Orphanet:2623	Geleophysic dysplasia
LTBP3	Orphanet:2899	Brachyolmia-amelogenesis imperfecta syndrome
LTBP3	Orphanet:969	Acromicric dysplasia

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
LTBP2	HGNC:6715	ENSG00000119681	Q14767	Latent-transforming growth factor beta-binding protein 2	gencc,clinvar
LTBP3	HGNC:6716	ENSG00000168056	Q9NS15	Latent-transforming growth factor beta-binding protein 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LTBP2	Latent-transforming growth factor beta-binding protein 2	May play an integral structural role in elastic-fiber architectural organization and/or assembly.
LTBP3	Latent-transforming growth factor beta-binding protein 3	Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space.

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)
LTBP2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
LTBP3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

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
ascending aorta	2
descending thoracic aorta	2
thoracic aorta	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LTBP2	276	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta
LTBP3	279	broad	marker	descending thoracic aorta, thoracic aorta, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LTBP2	2,658
LTBP3	2,339

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LTBP3	Q9NS15	64.21
LTBP2	Q14767	58.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 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
Elastic fibre formation	2	335.9×	2e-05	LTBP2, LTBP3
TGF-beta receptor signaling activates SMADs	2	326.3×	2e-05	LTBP2, LTBP3
Molecules associated with elastic fibres	2	308.6×	2e-05	LTBP2, LTBP3
Signaling by TGF-beta Receptor Complex	2	200.3×	4e-05	LTBP2, LTBP3
Signaling by TGFB family members	2	115.3×	1e-04	LTBP2, LTBP3
Extracellular matrix organization	2	63.1×	3e-04	LTBP2, LTBP3
Signal Transduction	2	10.2×	0.010	LTBP2, LTBP3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
transforming growth factor beta receptor signaling pathway	2	159.0×	5e-04	LTBP2, LTBP3
positive regulation of mesenchymal stem cell differentiation	1	1203.7×	0.003	LTBP3
lung saccule development	1	1053.2×	0.003	LTBP3
positive regulation of mesenchymal stem cell proliferation	1	1053.2×	0.003	LTBP3
supramolecular fiber organization	1	526.6×	0.004	LTBP2
positive regulation of bone resorption	1	495.6×	0.004	LTBP3
negative regulation of bone mineralization	1	468.1×	0.004	LTBP3
bone remodeling	1	468.1×	0.004	LTBP3
negative regulation of chondrocyte differentiation	1	337.0×	0.005	LTBP3
bone morphogenesis	1	300.9×	0.005	LTBP3
protein targeting	1	183.2×	0.007	LTBP2
chondrocyte differentiation	1	150.5×	0.008	LTBP3
bone mineralization	1	135.9×	0.008	LTBP3
protein secretion	1	131.7×	0.008	LTBP2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
LTBP2	0	0
LTBP3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	LTBP2, LTBP3

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)
LTBP2	0	—
LTBP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.