Leber congenital amaurosis 6

Summary

Leber congenital amaurosis 6 (MONDO:0013446) is a disease caused by RPGRIP1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: RPGRIP1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 982

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis 6
Mondo ID	MONDO:0013446
MeSH	C565327
OMIM	613826
DOID	DOID:0110329
UMLS	C1854260
MedGen	344245
GARD	0010490
Is cancer (heuristic)	no

Also known as: LCA6 · Leber congenital amaurosis 6 · Leber congenital amaurosis caused by mutation in RPGRIP1 · Leber congenital amaurosis type 6 · RPGRIP1 Leber congenital amaurosis

Data availability: 982 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 6

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 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:

302 uncertain significance, 208 likely benign, 50 pathogenic, 14 conflicting classifications of pathogenicity, 11 likely pathogenic, 6 benign, 6 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075073	NC_000014.8:g.(?21756136)(22005055_?)del	CHD8	Pathogenic	criteria provided, single submitter
1069706	NM_020366.4(RPGRIP1):c.711del (p.Lys239fs)	RPGRIP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069749	NM_020366.4(RPGRIP1):c.14_29dup (p.Asp11fs)	RPGRIP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073081	NC_000014.8:g.(?21795782)(21795966_?)del	RPGRIP1	Pathogenic	criteria provided, single submitter
1073082	NC_000014.8:g.(?21798388)(21798566_?)del	RPGRIP1	Pathogenic	criteria provided, single submitter
1074385	NM_020366.4(RPGRIP1):c.1363del (p.Glu455fs)	RPGRIP1	Pathogenic	criteria provided, single submitter
1074924	NM_020366.4(RPGRIP1):c.313C>T (p.Gln105Ter)	RPGRIP1	Pathogenic	criteria provided, single submitter
1357904	NM_020366.4(RPGRIP1):c.663dup (p.Asn222Ter)	RPGRIP1	Pathogenic	criteria provided, single submitter
1369938	NM_020366.4(RPGRIP1):c.2024del (p.Leu675fs)	RPGRIP1	Pathogenic	criteria provided, single submitter
1375717	NM_020366.4(RPGRIP1):c.1111C>T (p.Arg371Ter)	RPGRIP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1382627	NM_020366.4(RPGRIP1):c.1145T>A (p.Leu382Ter)	RPGRIP1	Pathogenic	criteria provided, single submitter
1387428	NM_020366.4(RPGRIP1):c.1867C>T (p.Gln623Ter)	RPGRIP1	Pathogenic	criteria provided, single submitter
1395639	NM_020366.4(RPGRIP1):c.2308_2311del (p.Lys770fs)	RPGRIP1	Pathogenic	criteria provided, single submitter
1415268	NM_020366.4(RPGRIP1):c.931-2_935delinsT	RPGRIP1	Pathogenic	criteria provided, single submitter
1436742	NM_020366.4(RPGRIP1):c.3617+1G>T	RPGRIP1	Pathogenic	criteria provided, single submitter
1437865	NM_020366.4(RPGRIP1):c.3275_3276dup (p.Ala1093fs)	RPGRIP1	Pathogenic	criteria provided, single submitter
1451134	NM_020366.4(RPGRIP1):c.898del (p.Val300fs)	RPGRIP1	Pathogenic	criteria provided, single submitter
1451517	NM_020366.4(RPGRIP1):c.808_826del (p.Ser269_Ile270insTer)	RPGRIP1	Pathogenic	criteria provided, single submitter
1452635	NM_020366.4(RPGRIP1):c.1995T>A (p.Cys665Ter)	RPGRIP1	Pathogenic	criteria provided, single submitter
1452857	NM_020366.4(RPGRIP1):c.3610C>T (p.Gln1204Ter)	RPGRIP1	Pathogenic	criteria provided, single submitter
1455333	NM_020366.4(RPGRIP1):c.767C>G (p.Ser256Ter)	RPGRIP1	Pathogenic	criteria provided, single submitter
1455614	NM_020366.4(RPGRIP1):c.1930C>T (p.Gln644Ter)	RPGRIP1	Pathogenic	criteria provided, single submitter
1456668	NC_000014.8:g.(?21785835)(21788356_?)del	RPGRIP1	Pathogenic	criteria provided, single submitter
1458554	NM_020366.4(RPGRIP1):c.1089_1090dup (p.Val364fs)	RPGRIP1	Pathogenic	criteria provided, single submitter
1459285	NM_020366.4(RPGRIP1):c.282_283dup (p.Ala95fs)	RPGRIP1	Pathogenic	criteria provided, single submitter
1459438	NC_000014.8:g.(?21756136)(21756240_?)del	RPGRIP1	Pathogenic	criteria provided, single submitter
156380	NM_020366.4(RPGRIP1):c.1892A>T (p.His631Leu)	RPGRIP1	Pathogenic	no assertion criteria provided
156381	NM_020366.4(RPGRIP1):c.3565_3571del (p.Arg1189fs)	RPGRIP1	Pathogenic	criteria provided, single submitter
156387	NM_020366.4(RPGRIP1):c.832C>T (p.Arg278Ter)	RPGRIP1	Pathogenic	criteria provided, multiple submitters, no conflicts
156388	NM_020366.4(RPGRIP1):c.2356C>T (p.Gln786Ter)	RPGRIP1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
RPGRIP1	Definitive	Autosomal recessive	Leber congenital amaurosis 6	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RPGRIP1	Orphanet:1872	Cone rod dystrophy
RPGRIP1	Orphanet:564	Meckel syndrome
RPGRIP1	Orphanet:65	Leber congenital amaurosis
CHD8	Orphanet:261229	14q11.2 microduplication syndrome
CHD8	Orphanet:642675	CHD8 overgrowth syndrome
MKS1	Orphanet:110	Bardet-Biedl syndrome
MKS1	Orphanet:220493	Joubert syndrome with ocular defect
MKS1	Orphanet:475	Isolated Joubert syndrome
MKS1	Orphanet:564	Meckel 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
RPGRIP1	HGNC:13436	ENSG00000092200	Q96KN7	X-linked retinitis pigmentosa GTPase regulator-interacting protein 1	gencc,clinvar
CHD8	HGNC:20153	ENSG00000100888	Q9HCK8	ATP-dependent chromatin remodeler CHD8	clinvar
MKS1	HGNC:7121	ENSG00000011143	Q9NXB0	Tectonic-like complex member MKS1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPGRIP1	X-linked retinitis pigmentosa GTPase regulator-interacting protein 1	May function as scaffolding protein.
CHD8	ATP-dependent chromatin remodeler CHD8	ATP-dependent chromatin-remodeling factor, it slides nucleosomes along DNA; nucleosome sliding requires ATP.
MKS1	Tectonic-like complex member MKS1	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPGRIP1	Other/Unknown	no		C2_dom, C2-C2_1, RPGRIP1_fam
CHD8	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
MKS1	Other/Unknown	no		C2_B9-type_dom

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
left testis	1
right testis	1
sperm	1
cortical plate	1
sural nerve	1
ventricular zone	1
left ovary	1
olfactory segment of nasal mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPGRIP1	168	tissue_specific	marker	left testis, sperm, right testis
CHD8	283	ubiquitous	marker	sural nerve, ventricular zone, cortical plate
MKS1	182	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHD8	4,791
RPGRIP1	1,422
MKS1	1,087

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHD8	Q9HCK8	2
RPGRIP1	Q96KN7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MKS1	Q9NXB0	74.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.024	CHD8
Signaling by Hedgehog	1	92.1×	0.024	MKS1
Hedgehog ‘off’ state	1	89.2×	0.024	MKS1
CHD6, CHD7, CHD8, CHD9 subfamily	1	74.2×	0.024	CHD8
Anchoring of the basal body to the plasma membrane	1	56.5×	0.024	MKS1
Cilium Assembly	1	54.4×	0.024	MKS1
Organelle biogenesis and maintenance	1	33.0×	0.034	MKS1
Signal Transduction	1	5.1×	0.187	MKS1

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
non-motile cilium assembly	2	193.7×	0.001	RPGRIP1, MKS1
smoothened signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	5617.3×	0.003	MKS1
common bile duct development	1	1872.4×	0.007	MKS1
regulation of Wnt signaling pathway, planar cell polarity pathway	1	1123.5×	0.008	MKS1
negative regulation of fibroblast apoptotic process	1	802.5×	0.009	CHD8
retinal rod cell development	1	561.7×	0.010	RPGRIP1
epithelial structure maintenance	1	401.2×	0.010	MKS1
head development	1	401.2×	0.010	MKS1
cardiac septum morphogenesis	1	401.2×	0.010	MKS1
prepulse inhibition	1	374.5×	0.010	CHD8
positive regulation of transcription by RNA polymerase III	1	312.1×	0.010	CHD8
inner ear receptor cell stereocilium organization	1	280.9×	0.010	MKS1
dorsal/ventral neural tube patterning	1	267.5×	0.010	MKS1
embryonic brain development	1	267.5×	0.010	MKS1
branching morphogenesis of an epithelial tube	1	244.2×	0.010	MKS1
neural precursor cell proliferation	1	224.7×	0.010	RPGRIP1
regulation of smoothened signaling pathway	1	208.1×	0.010	MKS1
motile cilium assembly	1	193.7×	0.011	MKS1
regulation of canonical Wnt signaling pathway	1	181.2×	0.011	MKS1
digestive tract development	1	175.5×	0.011	CHD8
embryonic skeletal system development	1	130.6×	0.013	MKS1
embryonic digit morphogenesis	1	100.3×	0.017	MKS1
social behavior	1	90.6×	0.018	CHD8
determination of left/right symmetry	1	85.1×	0.018	MKS1
neural tube closure	1	62.4×	0.024	MKS1
negative regulation of canonical Wnt signaling pathway	1	39.3×	0.036	CHD8
Wnt signaling pathway	1	33.2×	0.041	CHD8
brain development	1	26.5×	0.046	CHD8
visual perception	1	26.5×	0.046	RPGRIP1
mRNA processing	1	26.2×	0.046	CHD8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

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
CHD8	1	2
RPGRIP1	0	0
MKS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	CHD8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CHD8	7	Binding:7

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	CHD8

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	1	CHD8
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RPGRIP1, MKS1

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)
RPGRIP1	0	—
MKS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.