Leber congenital amaurosis 2

Summary

Leber congenital amaurosis 2 (MONDO:0008765) is a disease caused by RPE65 (GenCC Definitive), with 3 cohort genes and 2 clinical trials.

At a glance

• Causal gene: RPE65 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 934
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis 2
Mondo ID	MONDO:0008765
MeSH	C536601
OMIM	204100
DOID	DOID:0110016
UMLS	C1859844
MedGen	348473
GARD	0000636
Is cancer (heuristic)	no

Also known as: amaurosis congenita of Leber, type 2 · LCA2 · Leber congenital amaurosis 2 · Leber congenital amaurosis caused by mutation in RPE65 · Leber congenital amaurosis type 2 · RPE65 Leber congenital amaurosis

Data availability: 934 ClinVar variants · 2 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 2

Related subtypes (20): retinal aplasia, Leber congenital amaurosis 1, Leber congenital amaurosis 3, Leber congenital amaurosis 4, Leber congenital amaurosis 5, 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

600 retrieved; paginated sample, class counts are floors:

313 likely benign, 143 uncertain significance, 78 pathogenic, 34 likely pathogenic, 16 pathogenic/likely pathogenic, 9 benign, 6 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1802541	NM_000329.3(RPE65):c.[1206G>A;1207_1210dup]		Pathogenic	criteria provided, single submitter
1067769	NM_000329.3(RPE65):c.3G>A (p.Met1Ile)	RPE65	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067786	NM_000329.3(RPE65):c.496-1G>A	RPE65	Pathogenic	reviewed by expert panel
1068757	NM_000329.3(RPE65):c.200T>G (p.Leu67Arg)	RPE65	Pathogenic	reviewed by expert panel
1068758	NM_000329.3(RPE65):c.94G>T (p.Gly32Cys)	RPE65	Pathogenic	criteria provided, multiple submitters, no conflicts
1069087	NM_000329.3(RPE65):c.943_950del (p.Ile315fs)	RPE65	Pathogenic	criteria provided, single submitter
1069898	NM_000329.3(RPE65):c.1399C>G (p.Pro467Ala)	RPE65	Pathogenic	reviewed by expert panel
1070055	NM_000329.3(RPE65):c.61del (p.Glu21fs)	RPE65	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070297	NM_000329.3(RPE65):c.912C>G (p.Tyr304Ter)	RPE65	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070754	NM_000329.3(RPE65):c.1409C>T (p.Pro470Leu)	RPE65	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070755	NM_000329.3(RPE65):c.886dup (p.Arg296fs)	RPE65	Pathogenic	reviewed by expert panel
1072065	NM_000329.3(RPE65):c.777dup (p.Asn260Ter)	RPE65	Pathogenic	criteria provided, single submitter
1072114	NM_000329.3(RPE65):c.1028T>G (p.Leu343Ter)	RPE65	Pathogenic	criteria provided, single submitter
1072483	NM_000329.3(RPE65):c.886del (p.Arg296fs)	RPE65	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074826	NM_000329.3(RPE65):c.545A>G (p.His182Arg)	RPE65	Pathogenic	reviewed by expert panel
1076002	NM_000329.3(RPE65):c.637C>T (p.Gln213Ter)	RPE65	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076977	NC_000001.10:g.(?68912383)(68912553_?)del	RPE65	Pathogenic	criteria provided, single submitter
1213913	NM_000329.3(RPE65):c.693C>A (p.Cys231Ter)	RPE65	Pathogenic	criteria provided, single submitter
1213914	NM_000329.3(RPE65):c.1451-2del	RPE65	Pathogenic	criteria provided, multiple submitters, no conflicts
1213917	NM_000329.3(RPE65):c.859del	RPE65	Pathogenic	reviewed by expert panel
1213919	NM_000329.3(RPE65):c.785_787del (p.Phe262_Lys263delinsTer)	RPE65	Pathogenic	criteria provided, single submitter
13114	NM_000329.3(RPE65):c.700C>T (p.Arg234Ter)	RPE65	Pathogenic	reviewed by expert panel
13115	NM_000329.3(RPE65):c.271C>T (p.Arg91Trp)	RPE65	Pathogenic	reviewed by expert panel
13117	NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr)	RPE65	Pathogenic	reviewed by expert panel
13118	NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser)	RPE65	Pathogenic	reviewed by expert panel
13120	NM_000329.3(RPE65):c.1543C>T (p.Arg515Trp)	RPE65	Pathogenic	reviewed by expert panel
1321180	NM_000329.3(RPE65):c.1451-1G>A	RPE65	Pathogenic	reviewed by expert panel
1355343	NM_000329.3(RPE65):c.46_49del (p.Phe16fs)	RPE65	Pathogenic	criteria provided, multiple submitters, no conflicts
1380598	NM_000329.3(RPE65):c.775dup (p.Ile259fs)	RPE65	Pathogenic	criteria provided, single submitter
1381188	NM_000329.3(RPE65):c.504_580del (p.Cys169fs)	RPE65	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 4 · 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
RPE65	Definitive	Autosomal recessive	Leber congenital amaurosis 2	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RPE65	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
RPE65	Orphanet:65	Leber congenital amaurosis
RPE65	Orphanet:791	Retinitis pigmentosa
CTNND1	Orphanet:1997	Blepharo-cheilo-odontic syndrome

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
RPE65	HGNC:10294	ENSG00000116745	Q16518	Retinoid isomerohydrolase	gencc,clinvar
DEPDC1	HGNC:22949	ENSG00000024526	Q5TB30	DEP domain-containing protein 1A	clinvar
CTNND1	HGNC:2515	ENSG00000198561	O60716	Catenin delta-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPE65	Retinoid isomerohydrolase	Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins.
DEPDC1	DEP domain-containing protein 1A	May be involved in transcriptional regulation as a transcriptional corepressor.
CTNND1	Catenin delta-1	Key regulator of cell-cell adhesion that associates with and regulates the cell adhesion properties of both C-, E- and N-cadherins, being critical for their surface stability.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPE65	Enzyme (other)	yes	3.1.1.64	Carotenoid_Oase
DEPDC1	Other/Unknown	no		DEP_dom, Rho_GTPase_activation_prot, WH-like_DNA-bd_sf
CTNND1	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold

Expression context

Cohort genes with no expression data: 0.

3 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
male germ line stem cell (sensu Vertebrata) in testis	2
ventricular zone	2
pigmented layer of retina	1
retina	1
primordial germ cell in gonad	1
esophagus mucosa	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPE65	92	tissue_specific	marker	pigmented layer of retina, retina, male germ line stem cell (sensu Vertebrata) in testis
DEPDC1	173	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
CTNND1	134	ubiquitous	marker	ventricular zone, esophagus mucosa, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTNND1	2,883
RPE65	1,414
DEPDC1	1,354

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CTNND1	O60716	2
DEPDC1	Q5TB30	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RPE65	Q16518	95.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 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
CDH11 homotypic and heterotypic interactions	1	815.7×	0.005	CTNND1
Regulation of CDH19 Expression and Function	1	713.8×	0.005	CTNND1
InlA-mediated entry of Listeria monocytogenes into host cells	1	634.4×	0.005	CTNND1
Regulation of CDH11 function	1	519.1×	0.005	CTNND1
Regulation of CDH1 Function	1	475.8×	0.005	CTNND1
The canonical retinoid cycle in rods (twilight vision)	1	259.6×	0.007	RPE65
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	248.3×	0.007	CTNND1
VEGFR2 mediated vascular permeability	1	203.9×	0.008	CTNND1
Visual phototransduction	1	129.8×	0.010	RPE65
Adherens junctions interactions	1	124.1×	0.010	CTNND1
Degradation of CDH1	1	98.5×	0.012	CTNND1
Activation of STAT3 by cadherin engagement	1	81.6×	0.013	CTNND1
Sensory Perception	1	47.6×	0.021	RPE65

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
zeaxanthin biosynthetic process	1	5617.3×	0.002	RPE65
negative regulation of blood vessel branching	1	5617.3×	0.002	CTNND1
positive regulation of protein localization to cell-cell junction	1	1872.4×	0.004	CTNND1
negative regulation of D-glucose transmembrane transport	1	1123.5×	0.005	CTNND1
vitamin A metabolic process	1	802.5×	0.005	RPE65
negative regulation of intracellular signal transduction	1	702.2×	0.005	CTNND1
retina homeostasis	1	374.5×	0.008	RPE65
neural retina development	1	312.1×	0.008	RPE65
retinal metabolic process	1	312.1×	0.008	RPE65
cell migration involved in sprouting angiogenesis	1	216.1×	0.009	CTNND1
detection of light stimulus involved in visual perception	1	216.1×	0.009	RPE65
retinoid metabolic process	1	165.2×	0.010	RPE65
regulation of postsynaptic membrane neurotransmitter receptor levels	1	165.2×	0.010	CTNND1
cell-cell adhesion mediated by cadherin	1	137.0×	0.011	CTNND1
circadian rhythm	1	81.4×	0.018	RPE65
cell-cell adhesion	1	33.8×	0.039	CTNND1
Wnt signaling pathway	1	33.2×	0.039	CTNND1
visual perception	1	26.5×	0.046	RPE65
protein stabilization	1	22.3×	0.051	CTNND1
intracellular signal transduction	1	12.7×	0.084	DEPDC1
negative regulation of DNA-templated transcription	1	10.5×	0.096	DEPDC1
negative regulation of transcription by RNA polymerase II	1	5.9×	0.160	CTNND1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RPE65	0	0
DEPDC1	0	0
CTNND1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CTNND1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPE65	3.1.1.64, 5.3.3.22	retinoid isomerohydrolase, lutein isomerase

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	1	RPE65
E	Difficult family or no structure, no drug	2	DEPDC1, CTNND1

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)
RPE65	0	—
DEPDC1	0	—
CTNND1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04525261	Not specified	COMPLETED	Natural History of Patients With Inherited Retinal Diseases Due to Mutations in RPE65 Gene