Leber congenital amaurosis 14

Summary

Leber congenital amaurosis 14 (MONDO:0013231) is a disease caused by LRAT (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: LRAT (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 101

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis 14
Mondo ID	MONDO:0013231
MeSH	C567636
OMIM	613341
DOID	DOID:0110188
UMLS	C2750063
MedGen	442375
GARD	0010883
Is cancer (heuristic)	no

Also known as: LCA14 · Leber congenital amaurosis 14 · Leber congenital amaurosis caused by mutation in LRAT · Leber congenital amaurosis type 14 · LRAT Leber congenital amaurosis · retinal dystrophy, early-onset severe

Data availability: 101 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 14

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 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

101 retrieved; paginated sample, class counts are floors:

76 uncertain significance, 8 conflicting classifications of pathogenicity, 6 benign/likely benign, 5 pathogenic, 3 pathogenic/likely pathogenic, 2 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
7907	NM_000350.3(ABCA4):c.6088C>T (p.Arg2030Ter)	ABCA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172717	NM_004744.5(LRAT):c.504C>A (p.Cys168Ter)	LRAT	Pathogenic	criteria provided, multiple submitters, no conflicts
1180621	NM_004744.5(LRAT):c.157_159dup (p.Val53dup)	LRAT	Pathogenic	criteria provided, multiple submitters, no conflicts
5336	NM_004744.5(LRAT):c.217_218del (p.Met73fs)	LRAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
817558	NM_004744.5(LRAT):c.139C>T (p.Arg47Ter)	LRAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
978446	NC_000004.12:g.(?154740841)(154749136_?)del	LRAT	Pathogenic	no assertion criteria provided
978449	NM_004744.5(LRAT):c.554_555del (p.Val185fs)	LRAT	Pathogenic	criteria provided, single submitter
978974	NM_004744.5(LRAT):c.241_242del (p.Leu81fs)	LRAT	Pathogenic	criteria provided, single submitter
978447	NM_004744.5(LRAT):c.481T>C (p.Cys161Arg)	LRAT	Likely pathogenic	no assertion criteria provided
978450	NM_004744.5(LRAT):c.149T>G (p.Val50Gly)	LRAT	Likely pathogenic	no assertion criteria provided
1065731	NM_004744.5(LRAT):c.316G>A (p.Ala106Thr)	LRAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1172716	NM_004744.5(LRAT):c.224C>T (p.Pro75Leu)	LRAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347850	NM_004744.5(LRAT):c.258G>A (p.Gly86=)	LRAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347852	NM_004744.5(LRAT):c.*98C>T	LRAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
425342	NM_004744.5(LRAT):c.487C>G (p.His163Asp)	LRAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
707021	NM_004744.5(LRAT):c.611C>T (p.Ala204Val)	LRAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802098	NM_004744.5(LRAT):c.346T>C (p.Phe116Leu)	LRAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902419	NM_004744.5(LRAT):c.519G>T (p.Pro173=)	LRAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002357	NM_004744.5(LRAT):c.382G>C (p.Asp128His)	LRAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
167259	NM_004744.5(LRAT):c.*3T>G	LRAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
2920628	NM_004744.5(LRAT):c.556A>C (p.Lys186Gln)	LRAT	Uncertain significance	no assertion criteria provided
3340096	NM_004744.5(LRAT):c.578G>T (p.Arg193Ile)	LRAT	Uncertain significance	criteria provided, single submitter
3362597	NM_004744.5(LRAT):c.676del (p.Leu226fs)	LRAT	Uncertain significance	criteria provided, single submitter
347845	NM_004744.5(LRAT):c.-115C>G	LRAT	Uncertain significance	criteria provided, single submitter
347846	NM_004744.5(LRAT):c.-84C>T	LRAT	Uncertain significance	criteria provided, single submitter
347847	NM_004744.5(LRAT):c.-2+7A>C	LRAT	Uncertain significance	criteria provided, single submitter
347848	NM_004744.5(LRAT):c.205C>T (p.Arg69Cys)	LRAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
347849	NM_004744.5(LRAT):c.244A>G (p.Thr82Ala)	LRAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
347851	NM_004744.5(LRAT):c.403G>T (p.Ala135Ser)	LRAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
347853	NM_004744.5(LRAT):c.*106T>C	LRAT	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 6 · 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
LRAT	Strong	Autosomal recessive	Leber congenital amaurosis 14	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LRAT	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
LRAT	Orphanet:65	Leber congenital amaurosis
LRAT	Orphanet:791	Retinitis pigmentosa
ABCA4	Orphanet:1872	Cone rod dystrophy
ABCA4	Orphanet:791	Retinitis pigmentosa
ABCA4	Orphanet:827	Stargardt disease

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
LRAT	HGNC:6685	ENSG00000121207	O95237	Lecithin retinol acyltransferase	gencc,clinvar
ABCA4	HGNC:34	ENSG00000198691	P78363	Retinal-specific phospholipid-transporting ATPase ABCA4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRAT	Lecithin retinol acyltransferase	Transfers the acyl group from the sn-1 position of phosphatidylcholine to all-trans retinol, producing all-trans retinyl esters.
ABCA4	Retinal-specific phospholipid-transporting ATPase ABCA4	Flippase that catalyzes in an ATP-dependent manner the transport of retinal-phosphatidylethanolamine conjugates like 11-cis and all-trans isomers of N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leafl…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	1	38.9×	0.051
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LRAT	Enzyme (other)	yes	2.3.1.135	LRAT_dom, LRAT
ABCA4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABCA4/ABCR

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
male germ line stem cell (sensu Vertebrata) in testis	2
pigmented layer of retina	2
primordial germ cell in gonad	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRAT	149	broad	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
ABCA4	164	tissue_specific	marker	pigmented layer of retina, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCA4	1,532
LRAT	900

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCA4	P78363	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRAT	O95237	83.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 2 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
Retinoid cycle disease events	2	2855.0×	5e-07	LRAT, ABCA4
Diseases associated with visual transduction	2	2855.0×	5e-07	LRAT, ABCA4
Diseases of the neuronal system	2	2855.0×	5e-07	LRAT, ABCA4
The canonical retinoid cycle in rods (twilight vision)	2	519.1×	1e-05	LRAT, ABCA4
Visual phototransduction	2	259.6×	4e-05	LRAT, ABCA4
Sensory Perception	2	95.2×	3e-04	LRAT, ABCA4
Defective visual phototransduction due to ABCA4 loss of function	1	5710.0×	4e-04	ABCA4
Defective visual phototransduction due to LRAT loss of function	1	2855.0×	7e-04	LRAT
Metabolism of fat-soluble vitamins	1	190.3×	0.009	LRAT
Disease	2	13.1×	0.009	LRAT, ABCA4
Retinoid metabolism and transport	1	124.1×	0.011	LRAT
ABC-family protein mediated transport	1	60.7×	0.020	ABCA4
Metabolism of vitamins and cofactors	1	58.3×	0.020	LRAT
Transport of small molecules	1	12.6×	0.083	ABCA4
Metabolism	1	5.8×	0.165	LRAT

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
retinoid metabolic process	2	495.6×	7e-05	LRAT, ABCA4
visual perception	2	79.5×	0.001	LRAT, ABCA4
positive regulation of lipid transport	1	4213.0×	0.001	LRAT
phospholipid transfer to membrane	1	2808.7×	0.002	ABCA4
vitamin A metabolic process	1	1203.7×	0.003	LRAT
phototransduction, visible light	1	648.1×	0.004	ABCA4
response to vitamin A	1	526.6×	0.005	LRAT
retinal metabolic process	1	468.1×	0.005	ABCA4
phospholipid translocation	1	312.1×	0.006	ABCA4
lipid storage	1	271.8×	0.006	LRAT
retinol metabolic process	1	247.8×	0.006	LRAT
response to retinoic acid	1	191.5×	0.007	LRAT
photoreceptor cell maintenance	1	179.3×	0.007	ABCA4
lipid transport	1	131.7×	0.009	ABCA4
response to bacterium	1	96.8×	0.012	LRAT
transmembrane transport	1	84.3×	0.013	ABCA4
cellular response to leukemia inhibitory factor	1	79.5×	0.013	LRAT

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LRAT	1	3
ABCA4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FRAMYCETIN	3	LRAT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LRAT	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LRAT	2.3.1.135	phosphatidylcholine-retinol O-acyltransferase

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

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)
FRAMYCETIN	3	LRAT

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	LRAT
C	Druggable family + PDB, no drug	1	ABCA4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ABCA4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.