Leber congenital amaurosis 10

Summary

Leber congenital amaurosis 10 (MONDO:0012723) is a disease caused by CEP290 (GenCC Strong), with 3 cohort genes and 6 clinical trials. Top therapeutic interventions include sepofarsen and brinretigene vesgedparvovec.

At a glance

• Causal gene: CEP290 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 811
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis 10
Mondo ID	MONDO:0012723
MeSH	C565720
OMIM	611755
DOID	DOID:0110291
UMLS	C1857821
MedGen	346672
GARD	0010487
Is cancer (heuristic)	no

Also known as: amaurosis congenita of Leber, type 10 · CEP290 Leber congenital amaurosis · LCA10 · Leber congenital amaurosis 10 · Leber congenital amaurosis caused by mutation in CEP290 · Leber congenital amaurosis type 10

Data availability: 811 ClinVar variants · 1 GenCC gene-disease record.

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 10

Related subtypes (20): retinal aplasia, Leber congenital amaurosis 1, Leber congenital amaurosis 2, Leber congenital amaurosis 3, Leber congenital amaurosis 4, Leber congenital amaurosis 5, Leber congenital amaurosis 9, Leber congenital amaurosis 12, 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:

311 uncertain significance, 76 conflicting classifications of pathogenicity, 68 pathogenic/likely pathogenic, 65 likely pathogenic, 35 pathogenic, 33 likely benign, 8 benign/likely benign, 4 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032903	NM_025114.4(CEP290):c.2632del (p.Ile878fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069520	NM_025114.4(CEP290):c.3488_3494dup (p.Val1166fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069579	NM_025114.4(CEP290):c.5235_5238del (p.Ser1745fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069582	NM_025114.4(CEP290):c.4090G>T (p.Glu1364Ter)	CEP290	Pathogenic	criteria provided, multiple submitters, no conflicts
1071036	NM_025114.4(CEP290):c.3708dup (p.Arg1237fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071910	NM_025114.4(CEP290):c.7324G>T (p.Glu2442Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071911	NM_025114.4(CEP290):c.1254_1255del (p.Lys419fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073200	NM_025114.4(CEP290):c.1060C>T (p.Gln354Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074481	NM_025114.4(CEP290):c.1258dup (p.Thr420fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074486	NM_025114.4(CEP290):c.4983del (p.Lys1661_Val1662insTer)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074543	NM_025114.4(CEP290):c.5788_5792del (p.Lys1930fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074952	NM_025114.4(CEP290):c.2213del (p.Asn737_Leu738insTer)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075280	NM_025114.4(CEP290):c.583_584del (p.Leu195fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075391	NM_025114.4(CEP290):c.5941G>T (p.Glu1981Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075924	NM_025114.4(CEP290):c.7282_7283dup (p.Tyr2429fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1185813	NM_025114.4(CEP290):c.712G>T (p.Glu238Ter)	CEP290	Pathogenic	criteria provided, multiple submitters, no conflicts
1213970	NM_025114.4(CEP290):c.133_136del (p.Gln45fs)	CEP290	Pathogenic	criteria provided, single submitter
126260	NM_025114.4(CEP290):c.4621del (p.Thr1541fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333	NM_025114.4(CEP290):c.5668G>T (p.Gly1890Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1337	NM_025114.4(CEP290):c.2991+1655A>G	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338	NM_025114.4(CEP290):c.2249T>G (p.Leu750Ter)	CEP290	Pathogenic	criteria provided, multiple submitters, no conflicts
1339	NM_025114.4(CEP290):c.4723A>T (p.Lys1575Ter)	CEP290	Pathogenic	criteria provided, multiple submitters, no conflicts
1339724	NM_025114.4(CEP290):c.7198C>T (p.Gln2400Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342	NM_025114.4(CEP290):c.613C>T (p.Arg205Ter)	CEP290	Pathogenic	criteria provided, multiple submitters, no conflicts
1343	NM_025114.4(CEP290):c.1260_1264del (p.Lys421fs)	CEP290	Pathogenic	no assertion criteria provided
1345	NM_025114.4(CEP290):c.5704G>T (p.Glu1902Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1381343	NM_025114.4(CEP290):c.4737del (p.Asp1580fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1385952	NM_025114.4(CEP290):c.3240T>A (p.Tyr1080Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387697	NM_025114.4(CEP290):c.7263dup (p.Glu2422Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1400998	NM_025114.4(CEP290):c.1750del (p.Ser584fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 14 · 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
CEP290	Strong	Autosomal recessive	Leber congenital amaurosis 10	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CEP290	Orphanet:110	Bardet-Biedl syndrome
CEP290	Orphanet:2318	Joubert syndrome with oculorenal defect
CEP290	Orphanet:3156	Senior-Loken syndrome
CEP290	Orphanet:564	Meckel syndrome
CEP290	Orphanet:65	Leber congenital amaurosis
WT1	Orphanet:220	Denys-Drash syndrome
WT1	Orphanet:242	46,XY complete gonadal dysgenesis
WT1	Orphanet:251510	46,XY partial gonadal dysgenesis
WT1	Orphanet:3097	Meacham syndrome
WT1	Orphanet:347	Frasier syndrome
WT1	Orphanet:654	Nephroblastoma
WT1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
WT1	Orphanet:83469	Desmoplastic small round cell tumor
WT1	Orphanet:893	WAGR 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
CEP290	HGNC:29021	ENSG00000198707	O15078	Centrosomal protein of 290 kDa	gencc,clinvar
WT1	HGNC:12796	ENSG00000184937	P19544	Wilms tumor protein	clinvar
RLIG1	HGNC:25322	ENSG00000133641	Q8N999	RNA ligase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CEP290	Centrosomal protein of 290 kDa	Involved in early and late steps in cilia formation.
WT1	Wilms tumor protein	Transcription factor that plays an important role in cellular development and cell survival.
RLIG1	RNA ligase 1	Functions as an RNA ligase, in vitro.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CEP290	Other/Unknown	no		Cep290, Cep209_CC5
WT1	Transcription factor	no		Wilms_tumour_N, Znf_C2H2_type, Znf_C2H2_sf
RLIG1	Other/Unknown	no		RLIG1

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	1
right uterine tube	1
ventricular zone	1
germinal epithelium of ovary	1
metanephric glomerulus	1
renal glomerulus	1
Brodmann (1909) area 23	1
endothelial cell	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CEP290	278	ubiquitous	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone
WT1	168	broad	marker	germinal epithelium of ovary, renal glomerulus, metanephric glomerulus
RLIG1	288	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WT1	3,938
CEP290	2,778
RLIG1	506

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WT1	P19544	28

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RLIG1	Q8N999	92.03
CEP290	O15078	60.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
Nephron development	1	439.2×	0.029	WT1
Transcriptional regulation of testis differentiation	1	356.9×	0.029	WT1
Centrosome maturation	1	126.9×	0.029	CEP290
Loss of Nlp from mitotic centrosomes	1	79.3×	0.029	CEP290
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.029	CEP290
AURKA Activation by TPX2	1	76.1×	0.029	CEP290
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.029	CEP290
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.029	CEP290
Mitotic G2-G2/M phases	1	63.4×	0.029	CEP290
G2/M Transition	1	63.4×	0.029	CEP290
Negative Regulation of CDH1 Gene Transcription	1	60.1×	0.029	WT1
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.029	CEP290
Anchoring of the basal body to the plasma membrane	1	56.5×	0.029	CEP290
Cilium Assembly	1	54.4×	0.029	CEP290
Mitotic Prometaphase	1	34.6×	0.039	CEP290
Organelle biogenesis and maintenance	1	33.0×	0.039	CEP290
M Phase	1	33.0×	0.039	CEP290
Cell Cycle, Mitotic	1	24.1×	0.050	CEP290
Cell Cycle	1	18.0×	0.063	CEP290
Innate Immune System	1	12.8×	0.085	CEP290
Neutrophil degranulation	1	11.5×	0.089	CEP290
Immune System	1	6.5×	0.148	CEP290

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
camera-type eye development	2	239.0×	0.001	CEP290, WT1
negative regulation of metanephric glomerular mesangial cell proliferation	1	5617.3×	0.003	WT1
regulation of animal organ formation	1	2808.7×	0.003	WT1
adrenal cortex formation	1	2808.7×	0.003	WT1
visceral serous pericardium development	1	2808.7×	0.003	WT1
posterior mesonephric tubule development	1	2808.7×	0.003	WT1
obsolete ciliary basal body-plasma membrane docking	1	2808.7×	0.003	CEP290
positive regulation of metanephric ureteric bud development	1	2808.7×	0.003	WT1
kidney development	2	93.6×	0.003	CEP290, WT1
RNA repair	1	1872.4×	0.003	RLIG1
ciliary transition zone assembly	1	1872.4×	0.003	CEP290
positive regulation of heart growth	1	1404.3×	0.003	WT1
metanephric S-shaped body morphogenesis	1	1404.3×	0.003	WT1
negative regulation of female gonad development	1	1404.3×	0.003	WT1
thorax and anterior abdomen determination	1	1123.5×	0.003	WT1
cardiac muscle cell fate commitment	1	1123.5×	0.003	WT1
metanephric epithelium development	1	1123.5×	0.003	WT1
cellular response to gonadotropin stimulus	1	936.2×	0.004	WT1
pronephros development	1	802.5×	0.004	CEP290
regulation of establishment of protein localization	1	802.5×	0.004	CEP290
metanephric mesenchyme development	1	802.5×	0.004	WT1
otic vesicle formation	1	702.2×	0.004	CEP290
tissue development	1	624.1×	0.004	WT1
diaphragm development	1	624.1×	0.004	WT1
sex determination	1	561.7×	0.004	WT1
positive regulation of male gonad development	1	561.7×	0.004	WT1
glomerular basement membrane development	1	510.7×	0.004	WT1
mesenchymal to epithelial transition	1	510.7×	0.004	WT1
podocyte differentiation	1	468.1×	0.005	WT1
glomerulus development	1	432.1×	0.005	WT1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CEP290	0	0
WT1	0	0
RLIG1	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	CEP290, WT1, RLIG1

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)
CEP290	0	—
WT1	0	—
RLIG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	2
PHASE1/PHASE2	2
PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03913143	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Efficacy, Safety, Tolerability and Exposure After a Repeat-dose of Sepofarsen (QR-110) in LCA10 (ILLUMINATE)
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT03913130	PHASE1/PHASE2	TERMINATED	Extension Study to Study PQ-110-001 (NCT03140969)
NCT03396042	Not specified	COMPLETED	Natural History Study of CEP290-Related Retinal Degeneration

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SEPOFARSEN	2	4
BRINRETIGENE VESGEDPARVOVEC	2	1