glaucoma 3, primary congenital, D

Summary

glaucoma 3, primary congenital, D (MONDO:0013122) is a disease caused by LTBP2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: LTBP2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 240

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glaucoma 3, primary congenital, D
Mondo ID	MONDO:0013122
MeSH	C567765
OMIM	613086
UMLS	C2751316
MedGen	416524
GARD	0018226
Is cancer (heuristic)	no

Also known as: glaucoma 3, primary congenital, D · glaucoma 3, primary congenital, type D · GLC3D

Data availability: 240 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary glaucoma › congenital glaucoma › primary congenital glaucoma › glaucoma 3, primary congenital, D

Related subtypes (2): glaucoma 3, primary congenital, C, CYP1B1-related glaucoma with or without anterior segment dysgenesis

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

240 retrieved; paginated sample, class counts are floors:

120 uncertain significance, 82 conflicting classifications of pathogenicity, 16 benign/likely benign, 12 benign, 5 pathogenic, 4 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
126959	NM_000428.3(LTBP2):c.5376del (p.Cys1793fs)	LTBP2	Pathogenic	no assertion criteria provided
2110814	NM_000428.3(LTBP2):c.3638dup (p.Thr1214fs)	LTBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7554	NM_000428.3(LTBP2):c.895C>T (p.Arg299Ter)	LTBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
7556	NM_000428.3(LTBP2):c.1243_1256del (p.Glu415fs)	LTBP2	Pathogenic	no assertion criteria provided
7557	NM_000428.3(LTBP2):c.331C>T (p.Gln111Ter)	LTBP2	Pathogenic	no assertion criteria provided
7559	NM_000428.3(LTBP2):c.1417del (p.Leu473fs)	LTBP2	Pathogenic	no assertion criteria provided
1507148	NM_000428.3(LTBP2):c.2389-2A>G	LTBP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065137	NM_000428.3(LTBP2):c.565+1G>A	LTBP2	Likely pathogenic	criteria provided, single submitter
31630	NM_000428.3(LTBP2):c.4313G>A (p.Cys1438Tyr)	LTBP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
7555	NM_000428.3(LTBP2):c.412del (p.Ala138fs)	LTBP2	Likely pathogenic	criteria provided, single submitter
126949	NM_000428.3(LTBP2):c.1295C>T (p.Pro432Leu)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126955	NM_000428.3(LTBP2):c.4250A>G (p.Gln1417Arg)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1301847	NM_000428.3(LTBP2):c.4978G>T (p.Gly1660Trp)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
132836	NM_000428.3(LTBP2):c.3527-14T>C	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1354646	NM_000428.3(LTBP2):c.654C>T (p.Cys218=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1380286	NM_000428.3(LTBP2):c.4620C>T (p.Gly1540=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314269	NM_000428.3(LTBP2):c.4869G>A (p.Leu1623=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314270	NM_000428.3(LTBP2):c.4821G>A (p.Thr1607=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314271	NM_000428.3(LTBP2):c.4621G>A (p.Glu1541Lys)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314272	NM_000428.3(LTBP2):c.4516G>A (p.Val1506Met)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314273	NM_000428.3(LTBP2):c.4476C>T (p.Phe1492=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314274	NM_000428.3(LTBP2):c.4467T>C (p.Cys1489=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314276	NM_000428.3(LTBP2):c.4203G>A (p.Thr1401=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314278	NM_000428.3(LTBP2):c.3891G>A (p.Pro1297=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314281	NM_000428.3(LTBP2):c.3558C>T (p.Cys1186=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314282	NM_000428.3(LTBP2):c.3527-3C>A	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314283	NM_000428.3(LTBP2):c.3278-15G>A	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314286	NM_000428.3(LTBP2):c.3114G>A (p.Gln1038=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314290	NM_000428.3(LTBP2):c.2853G>A (p.Ser951=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314293	NM_000428.3(LTBP2):c.2789-9T>C	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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	Definitive	Autosomal recessive	microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma	20
LTBP3	Definitive	Autosomal recessive	microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma	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.