Leber congenital amaurosis 8

Summary

Leber congenital amaurosis 8 (MONDO:0013453) is a disease caused by CRB1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CRB1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,778

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis 8
Mondo ID	MONDO:0013453
OMIM	613835
DOID	DOID:0110079
UMLS	C3151202
MedGen	462552
GARD	0010881
Is cancer (heuristic)	no

Also known as: CRB1 Leber congenital amaurosis · LCA8 · Leber congenital amaurosis 8 · Leber congenital amaurosis caused by mutation in CRB1 · Leber congenital amaurosis type 8

Data availability: 1,778 ClinVar variants · 3 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 8

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 10, Leber congenital amaurosis 13, Leber congenital amaurosis 14, Leber congenital amaurosis 6, Leber congenital amaurosis 7, 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:

275 likely benign, 176 uncertain significance, 58 pathogenic, 37 likely pathogenic, 31 pathogenic/likely pathogenic, 17 conflicting classifications of pathogenicity, 6 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076360	NC_000001.10:g.(?196918585)(197742062_?)del	ASPM	Pathogenic	criteria provided, single submitter
1039551	NM_201253.3(CRB1):c.1522T>C (p.Cys508Arg)	CRB1	Pathogenic	criteria provided, single submitter
1045903	NM_201253.3(CRB1):c.3686G>C (p.Cys1229Ser)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065655	NM_201253.3(CRB1):c.18del (p.Asn7fs)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065687	NM_201253.3(CRB1):c.3427del (p.Cys1143fs)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065761	NM_201253.3(CRB1):c.3896del (p.Asp1299fs)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066344	NM_201253.3(CRB1):c.2105A>G (p.Tyr702Cys)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066707	NM_201253.3(CRB1):c.652+3_652+6del	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067463	NM_201253.3(CRB1):c.1439G>C (p.Cys480Ser)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067952	NM_201253.3(CRB1):c.2128+1G>C	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068031	NM_201253.3(CRB1):c.1349G>A (p.Cys450Tyr)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068463	NM_201253.3(CRB1):c.653-1G>A	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068576	NM_201253.3(CRB1):c.2942_2943del (p.Arg981fs)	CRB1	Pathogenic	criteria provided, single submitter
1069427	NM_201253.3(CRB1):c.1974_1990del (p.Ser659fs)	CRB1	Pathogenic	criteria provided, single submitter
1069458	NM_201253.3(CRB1):c.1078_1081del (p.Glu360fs)	CRB1	Pathogenic	criteria provided, single submitter
1070228	NM_201253.3(CRB1):c.2718G>A (p.Trp906Ter)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070332	NM_201253.3(CRB1):c.2767G>T (p.Glu923Ter)	CRB1	Pathogenic	criteria provided, single submitter
1070751	NM_201253.3(CRB1):c.3134del (p.Leu1045fs)	CRB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071809	NM_201253.3(CRB1):c.3860del (p.Pro1287fs)	CRB1	Pathogenic	criteria provided, single submitter
1071990	NM_201253.3(CRB1):c.3958C>T (p.Gln1320Ter)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072460	NM_201253.3(CRB1):c.2818C>T (p.Gln940Ter)	CRB1	Pathogenic	criteria provided, single submitter
1073128	NM_201253.3(CRB1):c.3887del (p.Lys1296fs)	CRB1	Pathogenic	criteria provided, single submitter
1073266	NM_201253.3(CRB1):c.1651C>T (p.Gln551Ter)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073987	NM_201253.3(CRB1):c.718C>T (p.Gln240Ter)	CRB1	Pathogenic	criteria provided, single submitter
1074341	NM_201253.3(CRB1):c.1700G>A (p.Trp567Ter)	CRB1	Pathogenic	criteria provided, single submitter
1074495	NM_201253.3(CRB1):c.4005+1G>C	CRB1	Pathogenic	criteria provided, single submitter
1074853	NM_201253.3(CRB1):c.962_966del (p.Asp321fs)	CRB1	Pathogenic	criteria provided, single submitter
1074871	NM_201253.3(CRB1):c.1743_1755dup (p.Ser586fs)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075122	NM_201253.3(CRB1):c.3325dup (p.Tyr1109fs)	CRB1	Pathogenic	criteria provided, single submitter
1075887	NM_201253.3(CRB1):c.770dup (p.Asp257fs)	CRB1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
CRB1	Definitive	Autosomal recessive	Leber congenital amaurosis 8	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRB1	Orphanet:251295	Pigmented paravenous retinochoroidal atrophy
CRB1	Orphanet:35612	Nanophthalmos
CRB1	Orphanet:65	Leber congenital amaurosis
CRB1	Orphanet:791	Retinitis pigmentosa
ASPM	Orphanet:2512	Autosomal recessive primary microcephaly

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
CRB1	HGNC:2343	ENSG00000134376	P82279	Protein crumbs homolog 1	gencc,clinvar
ASPM	HGNC:19048	ENSG00000066279	Q8IZT6	Abnormal spindle-like microcephaly-associated protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRB1	Protein crumbs homolog 1	Plays a role in photoreceptor morphogenesis in the retina.
ASPM	Abnormal spindle-like microcephaly-associated protein	Involved in mitotic spindle regulation and coordination of mitotic processes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRB1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
ASPM	Antibody/Immunoglobulin	yes		IQ_motif_EF-hand-BS, CH_dom, ARM-like

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
ventricular zone	2
endothelial cell	1
ganglionic eminence	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRB1	163	broad	marker	ganglionic eminence, ventricular zone, endothelial cell
ASPM	176	ubiquitous	marker	oocyte, ventricular zone, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASPM	2,949
CRB1	1,075

Intra-cohort edges

A	B	Sources
ASPM	CRB1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRB1	P82279	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ASPM	Q8IZT6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 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
negative regulation of asymmetric cell division	1	8426.0×	0.002	ASPM
camera-type eye photoreceptor cell development	1	8426.0×	0.002	CRB1
forebrain neuroblast division	1	4213.0×	0.002	ASPM
post-embryonic retina morphogenesis in camera-type eye	1	4213.0×	0.002	CRB1
establishment of bipolar cell polarity involved in cell morphogenesis	1	2808.7×	0.002	CRB1
meiotic spindle assembly	1	2808.7×	0.002	ASPM
spindle localization	1	1685.2×	0.003	ASPM
maintenance of centrosome location	1	1404.3×	0.003	ASPM
asymmetric cell division	1	1203.7×	0.003	ASPM
photoreceptor cell outer segment organization	1	526.6×	0.006	CRB1
cellular response to light stimulus	1	526.6×	0.006	CRB1
spindle organization	1	495.6×	0.006	ASPM
plasma membrane organization	1	443.5×	0.006	CRB1
glial cell differentiation	1	443.5×	0.006	CRB1
regulation of meiotic cell cycle	1	383.0×	0.006	ASPM
developmental growth	1	366.4×	0.006	ASPM
neuronal stem cell population maintenance	1	337.0×	0.006	ASPM
retina layer formation	1	324.1×	0.006	CRB1
detection of light stimulus involved in visual perception	1	324.1×	0.006	CRB1
positive regulation of neuroblast proliferation	1	290.6×	0.006	ASPM
establishment or maintenance of epithelial cell apical/basal polarity	1	290.6×	0.006	CRB1
establishment or maintenance of cell polarity	1	200.6×	0.008	CRB1
blood vessel remodeling	1	191.5×	0.008	CRB1
oogenesis	1	191.5×	0.008	ASPM
photoreceptor cell maintenance	1	179.3×	0.008	CRB1
heterophilic cell-cell adhesion	1	168.5×	0.008	CRB1
negative regulation of neuron differentiation	1	135.9×	0.010	ASPM
cerebral cortex development	1	102.8×	0.012	ASPM
male gonad development	1	78.0×	0.015	ASPM
positive regulation of canonical Wnt signaling pathway	1	77.3×	0.015	ASPM

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
CRB1	0	0
ASPM	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	1	ASPM
E	Difficult family or no structure, no drug	1	CRB1

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)
CRB1	0	—
ASPM	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.