Lymphatic malformation 4

Summary

Lymphatic malformation 4 (MONDO:0014393) is a disease caused by VEGFC (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: VEGFC (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lymphatic malformation 4
Mondo ID	MONDO:0014393
OMIM	615907
DOID	DOID:0070209
UMLS	C4747769
MedGen	1651756
GARD	0016468
Is cancer (heuristic)	no

Also known as: hereditary lymphedema caused by mutation in VEGFC · LMPH1D · lymphedema, hereditary, 1D · lymphedema, hereditary, type 1D · VEGFC hereditary lymphedema

Data availability: 10 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › lymphatic malformation › lymphatic malformation 4

Related subtypes (27): microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, lymphatic malformation 1, lymphatic malformation 5, yellow nail syndrome, lymphedema-distichiasis syndrome, campomelia, Cumming type, Dahlberg-Borer-Newcomer syndrome, Norman-Roberts syndrome, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, MPI-congenital disorder of glycosylation, hypotrichosis-lymphedema-telangiectasia syndrome, lymphatic malformation 2, lymphatic malformation 3, deafness-lymphedema-leukemia syndrome, lymphatic malformation 6, lymphatic malformation 7, Hennekam syndrome, Noonan syndrome, hypotrichosis-lymphedema-telangiectasia-renal defect syndrome, lymphatic malformation 10, lymphatic malformation 9, lymphatic malformation 11, lymphatic malformation 12, lymphatic malformation 8, congenital primary lymphedema of Gordon, lymphatic malformation 13, lymphatic malformation 14

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

10 retrieved; paginated sample, class counts are floors:

3 benign, 3 uncertain significance, 2 pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
140736	NM_005429.5(VEGFC):c.571_572insTT (p.Pro191fs)	VEGFC	Pathogenic	no assertion criteria provided
140737	NM_005429.5(VEGFC):c.628C>T (p.Arg210Ter)	VEGFC	Pathogenic	criteria provided, single submitter
3892839	NM_005429.5(VEGFC):c.961A>G (p.Asn321Asp)	HAFML	Uncertain significance	criteria provided, single submitter
3892838	NM_005429.5(VEGFC):c.181C>T (p.Arg61Trp)	VEGFC	Uncertain significance	criteria provided, single submitter
4279740	NM_005429.5(VEGFC):c.479A>G (p.Tyr160Cys)	VEGFC	Uncertain significance	criteria provided, single submitter
1806219	NM_005429.5(VEGFC):c.781G>A (p.Asp261Asn)	HAFML	Likely benign	criteria provided, single submitter
4685735	NM_005429.5(VEGFC):c.1227C>A (p.Val409=)	HAFML	Likely benign	criteria provided, single submitter
1330598	NM_005429.5(VEGFC):c.140A>T (p.Glu47Val)	VEGFC	Benign	criteria provided, multiple submitters, no conflicts
993883	NM_005429.5(VEGFC):c.364A>G (p.Ile122Val)	VEGFC	Benign	criteria provided, multiple submitters, no conflicts
994064	NM_005429.5(VEGFC):c.182G>A (p.Arg61Gln)	VEGFC	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
VEGFC	Strong	Autosomal dominant	lymphatic malformation 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VEGFC	Orphanet:569821	Congenital primary lymphedema of Gordon

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VEGFC	HGNC:12682	ENSG00000150630	P49767	Vascular endothelial growth factor C	gencc,clinvar
HAFML	HGNC:56694	ENSG00000248388		HuR (ELAVL1) associated fibroblast migratory lncRNA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VEGFC	Vascular endothelial growth factor C	Growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VEGFC	Other/Unknown	no		PDGF/VEGF_dom, CXCXC_repeat, PD_growth_factor_CS
HAFML	Other/Unknown	no

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
right lobe of thyroid gland	1
stromal cell of endometrium	1
thyroid gland	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VEGFC	224	ubiquitous	marker	stromal cell of endometrium, right lobe of thyroid gland, thyroid gland
HAFML	102		marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VEGFC	2,803
HAFML	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VEGFC	P49767	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
VEGF ligand-receptor interactions	1	1903.3×	0.001	VEGFC
VEGF binds to VEGFR leading to receptor dimerization	1	1268.9×	0.001	VEGFC
Platelet degranulation	1	87.8×	0.011	VEGFC

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 lymphangiogenesis	1	5617.3×	0.002	VEGFC
regulation of vascular endothelial growth factor receptor signaling pathway	1	2808.7×	0.002	VEGFC
substrate-dependent cell migration	1	2407.4×	0.002	VEGFC
positive regulation of mast cell chemotaxis	1	2407.4×	0.002	VEGFC
positive regulation of mesenchymal stem cell proliferation	1	2106.5×	0.002	VEGFC
morphogenesis of embryonic epithelium	1	1532.0×	0.003	VEGFC
vascular endothelial growth factor signaling pathway	1	1053.2×	0.003	VEGFC
induction of positive chemotaxis	1	991.3×	0.003	VEGFC
glial cell proliferation	1	887.0×	0.003	VEGFC
positive regulation of glial cell proliferation	1	702.2×	0.004	VEGFC
negative regulation of blood pressure	1	648.1×	0.004	VEGFC
positive regulation of neuroblast proliferation	1	581.1×	0.004	VEGFC
sprouting angiogenesis	1	481.5×	0.004	VEGFC
vascular endothelial growth factor receptor signaling pathway	1	481.5×	0.004	VEGFC
positive regulation of blood vessel endothelial cell migration	1	391.9×	0.004	VEGFC
positive regulation of protein secretion	1	343.9×	0.005	VEGFC
positive regulation of cell division	1	337.0×	0.005	VEGFC
negative regulation of osteoblast differentiation	1	295.6×	0.005	VEGFC
positive regulation of epithelial cell proliferation	1	244.2×	0.006	VEGFC
animal organ morphogenesis	1	191.5×	0.007	VEGFC
cellular response to leukemia inhibitory factor	1	159.0×	0.008	VEGFC
positive regulation of angiogenesis	1	115.4×	0.010	VEGFC
response to hypoxia	1	95.8×	0.012	VEGFC
response to xenobiotic stimulus	1	69.1×	0.016	VEGFC
positive regulation of cell population proliferation	1	33.6×	0.031	VEGFC
signal transduction	1	16.1×	0.062	VEGFC

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
VEGFC	0	0
HAFML	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	2	VEGFC, HAFML

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VEGFC	0	—
HAFML	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.