Leber congenital amaurosis 13

Summary

Leber congenital amaurosis 13 (MONDO:0012990) is a disease caused by RDH12 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: RDH12 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 571

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis 13
Mondo ID	MONDO:0012990
MeSH	C567197
OMIM	612712
DOID	DOID:0110330
UMLS	C2675186
MedGen	382544
GARD	0010882
Is cancer (heuristic)	no

Also known as: LCA13 · Leber congenital amaurosis 13 · Leber congenital amaurosis caused by mutation in RDH12 · Leber congenital amaurosis type 13 · RDH12 Leber congenital amaurosis

Data availability: 571 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 13

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 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

571 retrieved; paginated sample, class counts are floors:

250 likely benign, 156 uncertain significance, 51 pathogenic, 46 pathogenic/likely pathogenic, 41 likely pathogenic, 19 conflicting classifications of pathogenicity, 6 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067256	NM_152443.3(RDH12):c.278T>C (p.Leu93Pro)	GPHN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071004	NM_152443.3(RDH12):c.812_813del (p.Ala271fs)	GPHN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071767	NM_152443.3(RDH12):c.393T>A (p.Cys131Ter)	GPHN	Pathogenic	criteria provided, single submitter
1074472	NM_152443.3(RDH12):c.226G>C (p.Gly76Arg)	GPHN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1213889	NM_152443.3(RDH12):c.616G>A (p.Ala206Thr)	GPHN	Pathogenic/Likely pathogenic	criteria provided, single submitter
1451652	NM_152443.3(RDH12):c.52del (p.Met17_Val18insTer)	GPHN	Pathogenic	criteria provided, single submitter
1454036	NM_152443.3(RDH12):c.43del (p.Leu15fs)	GPHN	Pathogenic	criteria provided, single submitter
1515987	NM_152443.3(RDH12):c.133A>G (p.Thr45Ala)	GPHN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1516047	NM_152443.3(RDH12):c.505C>G (p.Arg169Gly)	GPHN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1929453	NM_152443.3(RDH12):c.723del (p.Ser242fs)	GPHN	Pathogenic	criteria provided, single submitter
1970808	NM_152443.3(RDH12):c.546del (p.Ile183fs)	GPHN	Pathogenic	criteria provided, multiple submitters, no conflicts
2046	NM_152443.3(RDH12):c.677A>G (p.Tyr226Cys)	GPHN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2047	NM_152443.3(RDH12):c.806_810del (p.Ala269fs)	GPHN	Pathogenic	criteria provided, multiple submitters, no conflicts
2048	NM_152443.3(RDH12):c.565C>T (p.Gln189Ter)	GPHN	Pathogenic	criteria provided, single submitter
2049	NM_152443.3(RDH12):c.146C>T (p.Thr49Met)	GPHN	Pathogenic	criteria provided, multiple submitters, no conflicts
2050	NM_152443.3(RDH12):c.184C>T (p.Arg62Ter)	GPHN	Pathogenic	criteria provided, multiple submitters, no conflicts
2051	NM_152443.3(RDH12):c.379G>T (p.Gly127Ter)	GPHN	Pathogenic	criteria provided, multiple submitters, no conflicts
2052	NM_152443.3(RDH12):c.451C>A (p.His151Asn)	GPHN	Pathogenic	no assertion criteria provided
2055	NM_152443.3(RDH12):c.295C>A (p.Leu99Ile)	GPHN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2056	NM_152443.3(RDH12):c.523T>C (p.Ser175Pro)	GPHN	Pathogenic	no assertion criteria provided
2058	NM_152443.3(RDH12):c.658+1G>A	GPHN	Pathogenic	criteria provided, multiple submitters, no conflicts
2059	NM_152443.3(RDH12):c.464C>T (p.Thr155Ile)	GPHN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678302	NM_152443.3(RDH12):c.617C>T (p.Ala206Val)	GPHN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678308	NM_152443.3(RDH12):c.779dup (p.Ala262fs)	GPHN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2697759	NM_152443.3(RDH12):c.807_813del (p.Leu270fs)	GPHN	Pathogenic	criteria provided, single submitter
2819003	NM_152443.3(RDH12):c.843C>G (p.Tyr281Ter)	GPHN	Pathogenic	criteria provided, single submitter
2866252	NM_152443.3(RDH12):c.216_219del (p.Asp72_Val73insTer)	GPHN	Pathogenic	criteria provided, single submitter
3648892	NM_152443.3(RDH12):c.352C>T (p.Gln118Ter)	GPHN	Pathogenic	criteria provided, single submitter
3652822	NM_152443.3(RDH12):c.792del (p.Ser265fs)	GPHN	Pathogenic	criteria provided, single submitter
3722862	NM_152443.3(RDH12):c.744_768del (p.Leu247_Trp248insTer)	GPHN	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
RDH12	Definitive	Autosomal recessive	Leber congenital amaurosis 13	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RDH12	Orphanet:65	Leber congenital amaurosis
RDH12	Orphanet:791	Retinitis pigmentosa
GPHN	Orphanet:308400	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C
GPHN	Orphanet:3197	Hereditary hyperekplexia
ZFYVE26	Orphanet:100996	Kjellin syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RDH12	HGNC:19977	ENSG00000139988	Q96NR8	Retinol dehydrogenase 12	gencc,clinvar
GPHN	HGNC:15465	ENSG00000171723	Q9NQX3	Gephyrin	clinvar
TMEM229B	HGNC:20130	ENSG00000198133	Q8NBD8	Transmembrane protein 229B	clinvar
ZFYVE26	HGNC:20761	ENSG00000072121	Q68DK2	Zinc finger FYVE domain-containing protein 26	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RDH12	Retinol dehydrogenase 12	Retinoids dehydrogenase/reductase with a clear preference for NADP.
GPHN	Gephyrin	Microtubule-associated protein involved in membrane protein-cytoskeleton interactions.
ZFYVE26	Zinc finger FYVE domain-containing protein 26	Phosphatidylinositol 3-phosphate-binding protein required for the abscission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abscission.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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	3.0×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RDH12	Enzyme (other)	yes	1.1.1.105	SDR_fam, NAD(P)-bd_dom_sf
GPHN	Other/Unknown	no		MoaB/Mog_dom, MoeA_linker/N, MoeA_C_domain_IV
TMEM229B	Other/Unknown	no		CmpB_TMEM229
ZFYVE26	Transcription factor	no		Znf_FYVE, Znf_FYVE_PHD, Znf_RING/FYVE/PHD

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	2
mammalian vulva	1
skin of leg	1
upper arm skin	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
cerebellum	1
lateral nuclear group of thalamus	1
endothelial cell	1
sural nerve	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RDH12	180	tissue_specific	marker	upper arm skin, skin of leg, mammalian vulva
GPHN	270	ubiquitous	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum
TMEM229B	204	broad	yes	lateral nuclear group of thalamus, cerebellar cortex, cerebellum
ZFYVE26	287	ubiquitous	marker	sural nerve, endothelial cell, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RDH12	3,526
GPHN	2,500
ZFYVE26	1,139
TMEM229B	450

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GPHN	Q9NQX3	1
ZFYVE26	Q68DK2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RDH12	Q96NR8	92.21
TMEM229B	Q8NBD8	90.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 4 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
Defective visual phototransduction due to RDH12 loss of function	1	5710.0×	5e-04	RDH12
Molybdenum cofactor biosynthesis	1	815.7×	0.002	GPHN
The canonical retinoid cycle in rods (twilight vision)	1	259.6×	0.004	RDH12

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycine receptor clustering	1	4213.0×	0.005	GPHN
establishment of synaptic specificity at neuromuscular junction	1	2106.5×	0.005	GPHN
gamma-aminobutyric acid receptor clustering	1	842.6×	0.006	GPHN
autophagosome organization	1	842.6×	0.006	ZFYVE26
Mo-molybdopterin cofactor biosynthetic process	1	601.9×	0.006	GPHN
cellular detoxification of aldehyde	1	526.6×	0.006	RDH12
response to metal ion	1	383.0×	0.007	GPHN
neurotransmitter receptor localization to postsynaptic specialization membrane	1	200.6×	0.012	GPHN
macrophage activation	1	175.5×	0.013	TMEM229B
retinoid metabolic process	1	123.9×	0.015	RDH12
retinol metabolic process	1	123.9×	0.015	RDH12
establishment of protein localization	1	108.0×	0.015	GPHN
regulation of cytokinesis	1	105.3×	0.015	ZFYVE26
photoreceptor cell maintenance	1	89.6×	0.016	RDH12
lysosome organization	1	76.6×	0.017	ZFYVE26
mitotic cytokinesis	1	64.8×	0.019	ZFYVE26
synapse assembly	1	57.7×	0.020	GPHN
response to bacterium	1	48.4×	0.023	TMEM229B
double-strand break repair via homologous recombination	1	39.0×	0.027	ZFYVE26
visual perception	1	19.9×	0.049	RDH12

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
RDH12	0	0
GPHN	0	0
TMEM229B	0	0
ZFYVE26	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RDH12	1.1.1.105, 1.1.1.300	all-trans-retinol dehydrogenase (NAD+), NADP-retinol dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	RDH12
E	Difficult family or no structure, no drug	3	GPHN, TMEM229B, ZFYVE26

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RDH12	0	—
GPHN	0	—
TMEM229B	0	—
ZFYVE26	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.