Myofibromatosis, infantile, 2

Summary

Myofibromatosis, infantile, 2 (MONDO:0014122) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 78

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myofibromatosis, infantile, 2
Mondo ID	MONDO:0014122
OMIM	615293
DOID	DOID:0070667
NCIT	C176944
UMLS	C3809084
MedGen	815414
GARD	0015939
Is cancer (heuristic)	no

Also known as: IMF2 · myofibromatosis caused by mutation in NOTCH3 · myofibromatosis, infantile 2 · myofibromatosis, infantile, 2 · myofibromatosis, infantile, type 2 · NOTCH3 myofibromatosis

Data availability: 78 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › mesenchymal cell neoplasm › pericytic neoplasm › benign perivascular tumor › infantile myofibromatosis › myofibromatosis, infantile, 2

Related subtypes (1): myofibromatosis, infantile, 1

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

78 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 16 conflicting classifications of pathogenicity, 15 benign/likely benign, 11 pathogenic/likely pathogenic, 7 likely benign, 5 pathogenic, 2 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
208501	NM_000435.3(NOTCH3):c.457C>T (p.Arg153Cys)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
2736837	NM_000435.3(NOTCH3):c.617G>A (p.Cys206Tyr)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374637	NM_000435.3(NOTCH3):c.1819C>T (p.Arg607Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447791	NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447794	NM_000435.3(NOTCH3):c.1672C>T (p.Arg558Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447825	NM_000435.3(NOTCH3):c.3062A>G (p.Tyr1021Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447832	NM_000435.3(NOTCH3):c.3296G>A (p.Cys1099Tyr)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447846	NM_000435.3(NOTCH3):c.421C>T (p.Arg141Cys)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
447849	NM_000435.3(NOTCH3):c.437G>A (p.Cys146Tyr)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
447862	NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
546089	NM_000435.3(NOTCH3):c.1630C>T (p.Arg544Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55850	NM_000435.3(NOTCH3):c.4556T>C (p.Leu1519Pro)	NOTCH3	Pathogenic	no assertion criteria provided
585596	NM_000435.3(NOTCH3):c.145T>G (p.Cys49Gly)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
811998	NM_000435.3(NOTCH3):c.316T>G (p.Cys106Gly)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9219	NM_000435.3(NOTCH3):c.505C>T (p.Arg169Cys)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
9225	NM_000435.3(NOTCH3):c.397C>T (p.Arg133Cys)	NOTCH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1508045	NM_000435.3(NOTCH3):c.1441G>T (p.Gly481Cys)	NOTCH3	Likely pathogenic	criteria provided, single submitter
2581716	NM_000435.3(NOTCH3):c.6409_6410del (p.Leu2137fs)	NOTCH3	Likely pathogenic	criteria provided, single submitter
1256515	NM_000435.3(NOTCH3):c.359C>T (p.Pro120Leu)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1299384	NM_000435.3(NOTCH3):c.2960C>G (p.Thr987Ser)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1384932	NM_000435.3(NOTCH3):c.2183G>A (p.Arg728His)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1678078	NM_000435.3(NOTCH3):c.1783G>A (p.Gly595Ser)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803285	NM_000435.3(NOTCH3):c.3970T>A (p.Cys1324Ser)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805895	NM_000435.3(NOTCH3):c.6620G>A (p.Arg2207Gln)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
447798	NM_000435.3(NOTCH3):c.1774C>A (p.Arg592Ser)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
702452	NM_000435.3(NOTCH3):c.2932A>C (p.Ser978Arg)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
766794	NM_000435.3(NOTCH3):c.224G>A (p.Arg75Gln)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
808490	NM_000435.3(NOTCH3):c.6619C>T (p.Arg2207Trp)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
808492	NM_000435.3(NOTCH3):c.3227G>A (p.Arg1076His)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
810777	NM_000435.3(NOTCH3):c.1345C>T (p.Arg449Cys)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
NOTCH3	Supportive	Autosomal dominant	infantile myofibromatosis	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOTCH3	Orphanet:136	Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy
NOTCH3	Orphanet:2591	Infantile myofibromatosis
NOTCH3	Orphanet:2789	Lateral meningocele syndrome

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
NOTCH3	HGNC:7883	ENSG00000074181	Q9UM47	Neurogenic locus notch homolog protein 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOTCH3	Neurogenic locus notch homolog protein 3	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOTCH3	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

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
popliteal artery	1
right coronary artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOTCH3	273	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH3	4,403

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH3	Q9UM47	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Defective LFNG causes SCDO3	1	2284.0×	0.002	NOTCH3
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	1903.3×	0.002	NOTCH3
Noncanonical activation of NOTCH3	1	1427.5×	0.002	NOTCH3
Pre-NOTCH Processing in Golgi	1	634.4×	0.003	NOTCH3
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.003	NOTCH3
NOTCH3 Intracellular Domain Regulates Transcription	1	439.2×	0.003	NOTCH3
Notch-HLH transcription pathway	1	407.9×	0.003	NOTCH3
Pre-NOTCH Transcription and Translation	1	122.8×	0.008	NOTCH3

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
glomerular capillary formation	1	5617.3×	0.002	NOTCH3
neuroblast differentiation	1	2106.5×	0.003	NOTCH3
neuron fate commitment	1	802.5×	0.004	NOTCH3
artery morphogenesis	1	674.1×	0.004	NOTCH3
forebrain development	1	351.1×	0.006	NOTCH3
positive regulation of smooth muscle cell proliferation	1	330.4×	0.006	NOTCH3
positive regulation of miRNA transcription	1	290.6×	0.006	NOTCH3
negative regulation of neuron differentiation	1	271.8×	0.006	NOTCH3
Notch signaling pathway	1	141.6×	0.009	NOTCH3
axon guidance	1	90.6×	0.013	NOTCH3
negative regulation of transcription by RNA polymerase II	1	17.7×	0.062	NOTCH3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	NOTCH3

Therapeutics

Drug target analysis

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

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
NOTCH3	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH3	3	Binding:3

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

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)
VAREGACESTAT	2	NOTCH3

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	NOTCH3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.