Leber congenital amaurosis 9

Summary

Leber congenital amaurosis 9 (MONDO:0012056) is a disease caused by NMNAT1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: NMNAT1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 202

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis 9
Mondo ID	MONDO:0012056
MeSH	C536603
OMIM	608553
DOID	DOID:0110005
UMLS	C1837873
MedGen	325277
GARD	0009491
Is cancer (heuristic)	no

Also known as: amaurosis congenita of Leber, type 9 · LCA9 · Leber congenital amaurosis 9 · Leber congenital amaurosis caused by mutation in NMNAT1 · Leber congenital amaurosis type 9 · NMNAT1 Leber congenital amaurosis

Data availability: 202 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 9

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 12, Leber congenital amaurosis 10, 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

202 retrieved; paginated sample, class counts are floors:

66 uncertain significance, 54 likely benign, 38 pathogenic, 21 likely pathogenic, 9 conflicting classifications of pathogenicity, 9 pathogenic/likely pathogenic, 3 benign/likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
978238	NM_022787.4(NMNAT1):c.-69C>T	LOC126805613	Pathogenic	no assertion criteria provided
1050789	NM_022787.4(NMNAT1):c.299+526_*968dup	NMNAT1	Pathogenic	no assertion criteria provided
1062684	NM_022787.4(NMNAT1):c.500A>G (p.Asn167Ser)	NMNAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071528	NC_000001.10:g.(?10027411)(10042759_?)del	NMNAT1	Pathogenic	criteria provided, single submitter
1412405	NM_022787.4(NMNAT1):c.393_394del (p.Glu131fs)	NMNAT1	Pathogenic	criteria provided, single submitter
1424174	NM_022787.4(NMNAT1):c.676del (p.Ile226fs)	NMNAT1	Pathogenic	criteria provided, single submitter
1426207	NC_000001.10:g.(?10035630)(10041248_?)del	NMNAT1	Pathogenic	criteria provided, single submitter
1435359	NM_022787.4(NMNAT1):c.116-2A>G	NMNAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1437729	NM_022787.4(NMNAT1):c.469del (p.Ala157fs)	NMNAT1	Pathogenic	criteria provided, single submitter
1451670	NC_000001.10:g.(?10041069)(10041248_?)del	NMNAT1	Pathogenic	criteria provided, single submitter
1459432	NM_022787.4(NMNAT1):c.255G>A (p.Trp85Ter)	NMNAT1	Pathogenic	criteria provided, single submitter
190977	NM_022787.4(NMNAT1):c.53A>G (p.Asn18Ser)	NMNAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2081952	NM_022787.4(NMNAT1):c.165C>G (p.Tyr55Ter)	NMNAT1	Pathogenic	criteria provided, single submitter
2131219	NM_022787.4(NMNAT1):c.648G>A (p.Trp216Ter)	NMNAT1	Pathogenic	criteria provided, single submitter
2426774	NC_000001.10:g.(?10032132)(10032266_?)del	NMNAT1	Pathogenic	criteria provided, single submitter
2426775	NC_000001.10:g.(?10032132)(10035853_?)del	NMNAT1	Pathogenic	criteria provided, single submitter
2426776	NC_000001.10:g.(?10027411)(10045246_?)del	NMNAT1	Pathogenic	criteria provided, single submitter
2426777	NC_000001.10:g.(?10041069)(10042759_?)del	NMNAT1	Pathogenic	criteria provided, single submitter
265453	NM_022787.4(NMNAT1):c.507G>A (p.Trp169Ter)	NMNAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
2733823	NM_022787.4(NMNAT1):c.721C>T (p.Pro241Ser)	NMNAT1	Pathogenic	criteria provided, single submitter
2856865	NM_022787.4(NMNAT1):c.282_283del (p.Glu94fs)	NMNAT1	Pathogenic	criteria provided, single submitter
2919586	NM_022787.4(NMNAT1):c.254G>A (p.Trp85Ter)	NMNAT1	Pathogenic	criteria provided, single submitter
3247741	NC_000001.11:g.(?9981031)(9982701_?)dup	NMNAT1	Pathogenic	criteria provided, single submitter
37132	NM_022787.4(NMNAT1):c.838T>C (p.Ter280Gln)	NMNAT1	Pathogenic	no assertion criteria provided
37133	NM_022787.4(NMNAT1):c.619C>T (p.Arg207Trp)	NMNAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
37134	NM_022787.4(NMNAT1):c.769G>A (p.Glu257Lys)	NMNAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37135	NM_022787.4(NMNAT1):c.817A>G (p.Asn273Asp)	NMNAT1	Pathogenic	no assertion criteria provided
37138	NM_022787.4(NMNAT1):c.710G>T (p.Arg237Leu)	NMNAT1	Pathogenic	no assertion criteria provided
37139	NM_022787.4(NMNAT1):c.457C>G (p.Leu153Val)	NMNAT1	Pathogenic	no assertion criteria provided
37140	NM_022787.4(NMNAT1):c.25G>A (p.Val9Met)	NMNAT1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
NMNAT1	Definitive	Autosomal recessive	Leber congenital amaurosis 9	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NMNAT1	Orphanet:1872	Cone rod dystrophy
NMNAT1	Orphanet:65	Leber congenital amaurosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NMNAT1	HGNC:17877	ENSG00000173614	Q9HAN9	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NMNAT1	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1	Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP.

Protein-family classification

Druggable: 1 · 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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NMNAT1	Enzyme (other)	yes	2.7.7.1	Cyt_trans-like, NadD/NMNAT, Rossmann-like_a/b/a_fold

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	1
mucosa of transverse colon	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NMNAT1	225	ubiquitous	yes	hindlimb stylopod muscle, muscle of leg, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NMNAT1	2,424

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NMNAT1	Q9HAN9	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nicotinate metabolism	1	393.8×	0.003	NMNAT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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 apoptotic DNA fragmentation	1	4213.0×	1e-03	NMNAT1
ATP generation from poly-ADP-D-ribose	1	4213.0×	1e-03	NMNAT1
nicotinamide metabolic process	1	3370.4×	1e-03	NMNAT1
nucleotide biosynthetic process	1	3370.4×	1e-03	NMNAT1
negative regulation of adipose tissue development	1	2407.4×	1e-03	NMNAT1
NAD+ biosynthetic process	1	1872.4×	1e-03	NMNAT1
NAD+ biosynthetic process via the salvage pathway	1	1872.4×	1e-03	NMNAT1
positive regulation of adipose tissue development	1	1053.2×	0.002	NMNAT1
response to wounding	1	221.7×	0.007	NMNAT1
negative regulation of neuron apoptotic process	1	110.9×	0.012	NMNAT1
positive regulation of MAPK cascade	1	80.6×	0.015	NMNAT1
negative regulation of DNA-templated transcription	1	31.6×	0.034	NMNAT1
positive regulation of DNA-templated transcription	1	27.9×	0.036	NMNAT1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NMNAT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NMNAT1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NMNAT1	2.7.7.1, 2.7.7.18	nicotinamide-nucleotide adenylyltransferase, nicotinate-nucleotide adenylyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	NMNAT1
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)
NMNAT1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.