Exudative vitreoretinopathy 4

Summary

Exudative vitreoretinopathy 4 (MONDO:0011151) is a disease caused by LRP5 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: LRP5 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 509

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	exudative vitreoretinopathy 4
Mondo ID	MONDO:0011151
MeSH	C566619
OMIM	601813
DOID	DOID:0111411
UMLS	C1866176
MedGen	356171
GARD	0015337
Is cancer (heuristic)	no

Also known as: EVR4 · exudative vitreoretinopathy 4 · exudative vitreoretinopathy type 4

Data availability: 509 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal vascular disorder › exudative vitreoretinopathy › LRP5-related exudative vitreoretinopathy › exudative vitreoretinopathy 4

Related subtypes (1): osteoporosis-pseudoglioma syndrome

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

509 retrieved; paginated sample, class counts are floors:

315 uncertain significance, 69 likely benign, 65 conflicting classifications of pathogenicity, 22 benign/likely benign, 18 likely pathogenic, 11 pathogenic/likely pathogenic, 5 pathogenic, 3 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179140	NM_002335.4(LRP5):c.2555C>T (p.Thr852Met)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1450334	NM_002335.4(LRP5):c.3122C>T (p.Thr1041Met)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1512510	NM_002335.4(LRP5):c.3236+2T>G	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191023	NM_002335.4(LRP5):c.685C>T (p.Arg229Trp)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1943870	NM_002335.4(LRP5):c.4263del (p.Phe1422fs)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225406	NM_002335.4(LRP5):c.593A>G (p.Asn198Ser)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2751235	NM_002335.4(LRP5):c.1372del (p.Leu458fs)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
287187	NM_002335.4(LRP5):c.2737dup (p.Cys913fs)	LRP5	Pathogenic	criteria provided, multiple submitters, no conflicts
3250483	NM_002335.4(LRP5):c.3915C>A (p.Cys1305Ter)	LRP5	Pathogenic	criteria provided, single submitter
3382244	NM_002335.4(LRP5):c.4479del (p.Tyr1494fs)	LRP5	Pathogenic	criteria provided, single submitter
520844	NM_002335.4(LRP5):c.2718_2721del (p.Met907fs)	LRP5	Pathogenic	criteria provided, multiple submitters, no conflicts
6269	NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter)	LRP5	Pathogenic	criteria provided, multiple submitters, no conflicts
6274	NM_002335.4(LRP5):c.1481G>A (p.Arg494Gln)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6287	NM_002335.4(LRP5):c.4488+2T>G	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
865885	NM_002335.4(LRP5):c.209_210delinsAA (p.Phe70Ter)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982560	NM_002335.4(LRP5):c.1270G>A (p.Asp424Asn)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184510	NM_002335.4(LRP5):c.3914G>A (p.Cys1305Tyr)	LRP5	Likely pathogenic	no assertion criteria provided
1520877	NM_002335.4(LRP5):c.1210G>A (p.Gly404Arg)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
162391	NM_002335.4(LRP5):c.3562C>T (p.Arg1188Trp)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687478	NM_002335.4(LRP5):c.4397del (p.Gly1466fs)	LRP5	Likely pathogenic	criteria provided, single submitter
1705512	NM_002335.4(LRP5):c.424_436del (p.Arg142fs)	LRP5	Likely pathogenic	criteria provided, single submitter
2085657	NM_002335.4(LRP5):c.1378G>A (p.Glu460Lys)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2152119	NM_002335.4(LRP5):c.3863A>G (p.Asp1288Gly)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572377	NM_002335.4(LRP5):c.853C>T (p.Gln285Ter)	LRP5	Likely pathogenic	criteria provided, single submitter
2572422	NM_002335.4(LRP5):c.440G>A (p.Trp147Ter)	LRP5	Likely pathogenic	criteria provided, single submitter
3391020	NM_002335.4(LRP5):c.592A>C (p.Asn198His)	LRP5	Likely pathogenic	criteria provided, single submitter
3573936	NM_002335.4(LRP5):c.4191_4192dup (p.Phe1398fs)	LRP5	Likely pathogenic	criteria provided, single submitter
3600191	NM_002335.4(LRP5):c.1264G>A (p.Ala422Thr)	LRP5	Likely pathogenic	criteria provided, single submitter
3600192	NM_002335.4(LRP5):c.1293C>G (p.Tyr431Ter)	LRP5	Likely pathogenic	criteria provided, single submitter
3600212	NM_002335.4(LRP5):c.2626G>A (p.Gly876Ser)	LRP5	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 9 · 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
LRP5	Definitive	Semidominant	exudative vitreoretinopathy 4	26

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LRP5	Orphanet:178377	Osteosclerosis-developmental delay-craniosynostosis syndrome
LRP5	Orphanet:2783	Autosomal dominant osteopetrosis type 1
LRP5	Orphanet:2788	Osteoporosis-pseudoglioma syndrome
LRP5	Orphanet:2790	Endosteal hyperostosis, Worth type
LRP5	Orphanet:2924	Isolated polycystic liver disease
LRP5	Orphanet:3416	Hyperostosis corticalis generalisata
LRP5	Orphanet:498481	LRP5-related primary osteoporosis
LRP5	Orphanet:891	Familial exudative vitreoretinopathy
LRP5	Orphanet:90050	Retinopathy of prematurity

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
LRP5	HGNC:6697	ENSG00000162337	O75197	Low-density lipoprotein receptor-related protein 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRP5	Low-density lipoprotein receptor-related protein 5	Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LRP5	Other/Unknown	no		LDLR_classB_rpt, EGF, LDrepeatLR_classA_rpt

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
ascending aorta	1
mucosa of transverse colon	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRP5	224	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRP5	2,619

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRP5	O75197	78.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Signaling by LRP5 mutants	1	1631.4×	0.004	LRP5
Signaling by RNF43 mutants	1	1268.9×	0.004	LRP5
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	713.8×	0.004	LRP5
Signaling by WNT in cancer	1	601.0×	0.004	LRP5
Regulation of FZD by ubiquitination	1	519.1×	0.004	LRP5
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	356.9×	0.005	LRP5
TCF dependent signaling in response to WNT	1	117.7×	0.012	LRP5
Signaling by WNT	1	112.0×	0.012	LRP5
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	LRP5
Disease	1	13.1×	0.084	LRP5
Signal Transduction	1	10.2×	0.098	LRP5

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
cell-cell signaling involved in mammary gland development	1	5617.3×	0.002	LRP5
mesodermal cell migration	1	3370.4×	0.002	LRP5
extracellular matrix-cell signaling	1	3370.4×	0.002	LRP5
anatomical structure regression	1	3370.4×	0.002	LRP5
Norrin signaling pathway	1	3370.4×	0.002	LRP5
apoptotic process involved in blood vessel morphogenesis	1	2808.7×	0.002	LRP5
establishment of blood-retinal barrier	1	2808.7×	0.002	LRP5
glucose catabolic process	1	2407.4×	0.002	LRP5
retinal blood vessel morphogenesis	1	2407.4×	0.002	LRP5
retina morphogenesis in camera-type eye	1	1872.4×	0.002	LRP5
cell migration involved in gastrulation	1	1532.0×	0.002	LRP5
bone marrow development	1	1532.0×	0.002	LRP5
osteoblast proliferation	1	1404.3×	0.002	LRP5
branching involved in mammary gland duct morphogenesis	1	1404.3×	0.002	LRP5
establishment of blood-brain barrier	1	1404.3×	0.002	LRP5
positive regulation of osteoblast proliferation	1	1203.7×	0.002	LRP5
osteoblast development	1	991.3×	0.002	LRP5
gastrulation with mouth forming second	1	936.2×	0.002	LRP5
bone remodeling	1	936.2×	0.002	LRP5
regulation of insulin secretion involved in cellular response to glucose stimulus	1	936.2×	0.002	LRP5
positive regulation of mesenchymal cell proliferation	1	601.9×	0.003	LRP5
bone morphogenesis	1	601.9×	0.003	LRP5
positive regulation of mitotic nuclear division	1	543.6×	0.004	LRP5
adipose tissue development	1	401.2×	0.004	LRP5
response to peptide hormone	1	391.9×	0.004	LRP5
amino acid transport	1	312.1×	0.005	LRP5
embryonic digit morphogenesis	1	300.9×	0.005	LRP5
positive regulation of fat cell differentiation	1	300.9×	0.005	LRP5
negative regulation of osteoblast differentiation	1	295.6×	0.005	LRP5
somatic stem cell population maintenance	1	247.8×	0.006	LRP5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
LRP5	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
LRP5	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LRP5

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)
LRP5	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.