Leber congenital amaurosis 5

Summary

Leber congenital amaurosis 5 (MONDO:0011473) is a disease caused by LCA5 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: LCA5 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 293
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis 5
Mondo ID	MONDO:0011473
MeSH	C536602
OMIM	604537
DOID	DOID:0110215
UMLS	C1858301
MedGen	388031
GARD	0009983
Is cancer (heuristic)	no

Also known as: amaurosis congenita of Leber, type 5 · LCA5 · LCA5 Leber congenital amaurosis · Leber congenital amaurosis 5 · Leber congenital amaurosis caused by mutation in LCA5 · Leber congenital amaurosis type 5

Data availability: 293 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › Leber congenital amaurosis › Leber congenital amaurosis 5

Related subtypes (20): retinal aplasia, Leber congenital amaurosis 1, Leber congenital amaurosis 2, Leber congenital amaurosis 3, Leber congenital amaurosis 4, Leber congenital amaurosis 9, Leber congenital amaurosis 12, Leber congenital amaurosis 10, Leber congenital amaurosis 13, Leber congenital amaurosis 14, Leber congenital amaurosis 6, Leber congenital amaurosis 7, Leber congenital amaurosis 8, Leber congenital amaurosis 11, Leber congenital amaurosis 15, Leber congenital amaurosis 16, Leber congenital amaurosis 17, Leber congenital amaurosis 19, Leber congenital amaurosis with early-onset deafness, Leber congenital amaurosis 18

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

293 retrieved; paginated sample, class counts are floors:

145 uncertain significance, 47 likely pathogenic, 26 pathogenic/likely pathogenic, 26 pathogenic, 22 conflicting classifications of pathogenicity, 15 likely benign, 10 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1009292	NM_001122769.3(LCA5):c.2T>C (p.Met1Thr)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068963	NM_001122769.3(LCA5):c.652C>T (p.Arg218Ter)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071921	NM_001122769.3(LCA5):c.1273del (p.Ala425fs)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073156	NM_001122769.3(LCA5):c.1378G>T (p.Glu460Ter)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172715	NM_001122769.3(LCA5):c.1368dup (p.Glu457fs)	LCA5	Pathogenic	criteria provided, multiple submitters, no conflicts
1323232	NM_001122769.3(LCA5):c.1062C>A (p.Tyr354Ter)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1430148	NM_001122769.3(LCA5):c.37del (p.Glu13fs)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452026	NM_001122769.3(LCA5):c.953dup (p.Asn318fs)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456840	NM_001122769.3(LCA5):c.69C>G (p.Tyr23Ter)	LCA5	Pathogenic	criteria provided, multiple submitters, no conflicts
1916309	NM_001122769.3(LCA5):c.766C>T (p.Gln256Ter)	LCA5	Pathogenic	criteria provided, multiple submitters, no conflicts
1965177	NM_001122769.3(LCA5):c.753_754del (p.Asn251fs)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2083359	NM_001122769.3(LCA5):c.1A>G (p.Met1Val)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2094552	NM_001122769.3(LCA5):c.407del (p.Ser135_Leu136insTer)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136441	NM_001122769.3(LCA5):c.42_45del (p.Lys15fs)	LCA5	Pathogenic	criteria provided, multiple submitters, no conflicts
2628020	NM_001122769.3(LCA5):c.346C>T (p.Gln116Ter)	LCA5	Pathogenic	criteria provided, single submitter
2676279	NM_001122769.3(LCA5):c.1550_1551del (p.Arg517fs)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676290	NM_001122769.3(LCA5):c.1730dup (p.Leu577fs)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2706899	NM_001122769.3(LCA5):c.609del (p.Leu203fs)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734917	NM_001122769.3(LCA5):c.721-1G>A	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2766428	NM_001122769.3(LCA5):c.110C>A (p.Ser37Ter)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
287456	NM_001122769.3(LCA5):c.1062C>G (p.Tyr354Ter)	LCA5	Pathogenic	criteria provided, multiple submitters, no conflicts
3241817	NM_001122769.3(LCA5):c.1823del (p.Leu608fs)	LCA5	Pathogenic	criteria provided, single submitter
3241823	NM_001122769.3(LCA5):c.69C>A (p.Tyr23Ter)	LCA5	Pathogenic	criteria provided, single submitter
374516	NM_001122769.3(LCA5):c.574dup (p.Thr192fs)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438153	NM_001122769.3(LCA5):c.838C>T (p.Arg280Ter)	LCA5	Pathogenic	criteria provided, multiple submitters, no conflicts
4816991	NM_001122769.3(LCA5):c.871_872del (p.Glu291fs)	LCA5	Pathogenic	criteria provided, single submitter
639813	NM_001122769.3(LCA5):c.190+1G>A	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
641484	NM_001122769.3(LCA5):c.1243G>T (p.Glu415Ter)	LCA5	Pathogenic	criteria provided, multiple submitters, no conflicts
662038	NM_001122769.3(LCA5):c.238C>T (p.Arg80Ter)	LCA5	Pathogenic	criteria provided, multiple submitters, no conflicts
802243	NM_001122769.3(LCA5):c.955G>A (p.Ala319Thr)	LCA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
LCA5	Definitive	Autosomal recessive	Leber congenital amaurosis 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LCA5	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
LCA5	Orphanet:65	Leber congenital amaurosis
POU1F1	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
POU1F1	Orphanet:231679	Isolated growth hormone deficiency type II
POU1F1	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LCA5	HGNC:31923	ENSG00000135338	Q86VQ0	Lebercilin	gencc,clinvar
SH3BGRL2	HGNC:15567	ENSG00000198478	Q9UJC5	SH3 domain-binding glutamic acid-rich-like protein 2	clinvar
POU1F1	HGNC:9210	ENSG00000064835	P28069	Pituitary-specific positive transcription factor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LCA5	Lebercilin	Involved in intraflagellar protein (IFT) transport in photoreceptor cilia.
POU1F1	Pituitary-specific positive transcription factor 1	Transcription factor involved in the specification of the lactotrope, somatotrope, and thyrotrope phenotypes in the developing anterior pituitary.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	1	5.8×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LCA5	Other/Unknown	no		Lebercilin-like, Lebercilin_dom
SH3BGRL2	Scaffold/PPI	no		Glut_rich_SH3-bd, Thioredoxin-like_sf, SH3BGR
POU1F1	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
bronchus	1
mucosa of paranasal sinus	1
esophagus squamous epithelium	1
ileal mucosa	1
parotid gland	1
adenohypophysis	1
decidua	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LCA5	214	ubiquitous	marker	mucosa of paranasal sinus, bronchial epithelial cell, bronchus
SH3BGRL2	249	ubiquitous	marker	parotid gland, ileal mucosa, esophagus squamous epithelium
POU1F1	73	tissue_specific	yes	pituitary gland, adenohypophysis, decidua

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POU1F1	1,170
LCA5	1,027
SH3BGRL2	522

Intra-cohort edges

A	B	Sources
LCA5	SH3BGRL2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SH3BGRL2	Q9UJC5	1
POU1F1	P28069	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LCA5	Q86VQ0	64.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 evidence-associated genes (0 with Reactome annotation).

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
adenohypophysis development	1	1203.7×	0.007	POU1F1
intraciliary transport	1	280.9×	0.016	LCA5
photoreceptor cell maintenance	1	179.3×	0.017	LCA5
protein transport	1	21.9×	0.084	LCA5
negative regulation of cell population proliferation	1	21.1×	0.084	POU1F1
regulation of DNA-templated transcription	1	15.8×	0.094	POU1F1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.141	POU1F1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.146	POU1F1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	POU1F1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
LCA5	0	0
SH3BGRL2	0	0
POU1F1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	LCA5, SH3BGRL2, POU1F1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LCA5	0	—
SH3BGRL2	0	—
POU1F1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05616793	PHASE1/PHASE2	RECRUITING	Safety and Tolerability Subretinal OPGx-001 for LCA5-Associated Inherited Retinal Degeneration (LCA5-IRD) and Non-interventional Arm With Untreated Patients