neurofibromatosis type 1 due to NF1 mutation or intragenic deletion

Summary

neurofibromatosis type 1 due to NF1 mutation or intragenic deletion (MONDO:0018208) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 4
• Phenotypes (HPO): 71

Clinical features

Signs & symptoms

Clinical features (HPO)

71 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000957	Cafe-au-lait spot	Very frequent (80-99%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000475	Broad neck	Frequent (30-79%)
HP:0000924	Abnormality of the skeletal system	Frequent (30-79%)
HP:0000997	Axillary freckling	Frequent (30-79%)
HP:0001176	Large hands	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0001833	Long foot	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0009088	Speech articulation difficulties	Frequent (30-79%)
HP:0009737	Lisch nodules	Frequent (30-79%)
HP:0011407	Proportionate tall stature	Frequent (30-79%)
HP:0012062	Bone cyst	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0030052	Inguinal freckling	Frequent (30-79%)
HP:0100698	Subcutaneous neurofibromas	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000276	Long face	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000324	Facial asymmetry	Occasional (5-29%)
HP:0000341	Narrow forehead	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000601	Hypotelorism	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002057	Prominent glabella	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002857	Genu valgum	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006479	Abnormality of the dental pulp	Occasional (5-29%)
HP:0009734	Optic nerve glioma	Occasional (5-29%)
HP:0009735	Spinal neurofibromas	Occasional (5-29%)
HP:0010794	Impaired visuospatial constructive cognition	Occasional (5-29%)
HP:0012210	Abnormal renal morphology	Occasional (5-29%)
HP:0012471	Thick vermilion border	Occasional (5-29%)
HP:0100697	Neurofibrosarcoma	Occasional (5-29%)
HP:0430022	Abnormality of the sphenoid sinus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
Mondo ID	MONDO:0018208
Orphanet	363700
UMLS	C5779636
MedGen	1842855
GARD	0017570
Is cancer (heuristic)	no

Also known as: Von Recklinghausen disease due to NF1 mutation or intragenic deletion

Data availability: 4 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › neurofibromatosis type 1 › neurofibromatosis type 1 due to NF1 mutation or intragenic deletion

Related subtypes (2): neurofibromatosis, familial spinal, chromosome 17q11.2 deletion syndrome, 1.4Mb

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

4 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
215990	NM_001042492.3(NF1):c.3974G>C (p.Arg1325Thr)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
355	NM_001042492.3(NF1):c.1523T>C (p.Leu508Pro)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4279519	NM_001042492.3(NF1):c.1155del (p.Arg385_Ile386insTer)	NF1	Likely pathogenic	criteria provided, single submitter
184363	NM_001042492.3(NF1):c.1137C>T (p.Cys379=)	NF1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma

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
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NF1	5,540

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NF1	P21359	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
RAS signaling downstream of NF1 loss-of-function variants	1	1631.4×	0.006	NF1
Oncogenic MAPK signaling	1	248.3×	0.015	NF1
Regulation of RAS by GAPs	1	193.6×	0.015	NF1
MAPK1/MAPK3 signaling	1	131.3×	0.017	NF1
MAPK family signaling cascades	1	102.9×	0.017	NF1
RAF/MAP kinase cascade	1	61.1×	0.023	NF1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	NF1
Disease	1	13.1×	0.086	NF1
Signal Transduction	1	10.2×	0.098	NF1

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
positive regulation of mast cell apoptotic process	1	16852.0×	0.002	NF1
regulation of glial cell differentiation	1	16852.0×	0.002	NF1
observational learning	1	16852.0×	0.002	NF1
gamma-aminobutyric acid secretion, neurotransmission	1	8426.0×	0.002	NF1
Schwann cell proliferation	1	5617.3×	0.002	NF1
forebrain astrocyte development	1	5617.3×	0.002	NF1
Schwann cell migration	1	5617.3×	0.002	NF1
glutamate secretion, neurotransmission	1	5617.3×	0.002	NF1
negative regulation of mast cell proliferation	1	5617.3×	0.002	NF1
negative regulation of Schwann cell migration	1	5617.3×	0.002	NF1
vascular associated smooth muscle cell migration	1	5617.3×	0.002	NF1
mast cell apoptotic process	1	4213.0×	0.002	NF1
negative regulation of Rac protein signal transduction	1	4213.0×	0.002	NF1
myeloid leukocyte migration	1	4213.0×	0.002	NF1
mast cell proliferation	1	3370.4×	0.002	NF1
amygdala development	1	2808.7×	0.002	NF1
regulation of blood vessel endothelial cell migration	1	2808.7×	0.002	NF1
vascular associated smooth muscle cell proliferation	1	2808.7×	0.002	NF1
negative regulation of Schwann cell proliferation	1	2407.4×	0.002	NF1
negative regulation of neurotransmitter secretion	1	2407.4×	0.002	NF1
hair follicle maturation	1	2106.5×	0.002	NF1
negative regulation of leukocyte migration	1	1685.2×	0.002	NF1
negative regulation of vascular associated smooth muscle cell migration	1	1685.2×	0.002	NF1
regulation of bone resorption	1	1532.0×	0.002	NF1
negative regulation of astrocyte differentiation	1	1532.0×	0.002	NF1
regulation of long-term synaptic potentiation	1	1532.0×	0.002	NF1
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	1532.0×	0.002	NF1
forebrain morphogenesis	1	1404.3×	0.002	NF1
regulation of cell-matrix adhesion	1	1296.3×	0.003	NF1
negative regulation of neuroblast proliferation	1	1203.7×	0.003	NF1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
NF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NF1

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)
NF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.