Lymphatic malformation 3

Summary

Lymphatic malformation 3 (MONDO:0013278) is a disease caused by GJC2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GJC2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lymphatic malformation 3
Mondo ID	MONDO:0013278
OMIM	613480
DOID	DOID:0070208
UMLS	C4747646
MedGen	1652857
GARD	0016456
Is cancer (heuristic)	no

Also known as: GJC2 hereditary lymphedema · hereditary lymphedema caused by mutation in GJC2 · LMPH1C · lymphedema, hereditary, 1C · lymphedema, hereditary, IC · lymphedema, hereditary, type 1C

Data availability: 21 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 3

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, deafness-lymphedema-leukemia syndrome, lymphatic malformation 4, 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

21 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 4 pathogenic, 3 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2079	NM_020435.4(GJC2):c.143C>T (p.Ser48Leu)	GJC2	Pathogenic	no assertion criteria provided
2080	NM_020435.4(GJC2):c.778C>T (p.Arg260Cys)	GJC2	Pathogenic	no assertion criteria provided
2202995	NM_020435.4(GJC2):c.-20+1G>C	GJC2	Pathogenic	criteria provided, multiple submitters, no conflicts
3362644	NM_020435.4(GJC2):c.401del (p.Gly134fs)	GJC2	Pathogenic	criteria provided, single submitter
656694	NM_020435.4(GJC2):c.1134_1144del (p.Ala379fs)	GJC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
445910	NM_020435.4(GJC2):c.1234C>T (p.His412Tyr)	GJC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625200	NM_020435.4(GJC2):c.107del (p.Ile36fs)	GJC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
872626	NM_020435.4(GJC2):c.1199C>A (p.Ala400Glu)	GJC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1697235	NM_020435.4(GJC2):c.148G>A (p.Glu50Lys)	GJC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2083600	NM_020435.4(GJC2):c.914dup (p.Ala306fs)	GJC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432123	NM_020435.4(GJC2):c.512A>C (p.Glu171Ala)	GJC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432126	NM_020435.4(GJC2):c.400G>A (p.Gly134Ser)	GJC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2671654	NM_020435.4(GJC2):c.32G>C (p.Arg11Pro)	GJC2	Uncertain significance	criteria provided, single submitter
2672149	NM_020435.4(GJC2):c.607C>T (p.Arg203Cys)	GJC2	Uncertain significance	criteria provided, single submitter
3064707	NM_020435.4(GJC2):c.619G>A (p.Glu207Lys)	GJC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3580792	NM_020435.4(GJC2):c.1162G>C (p.Gly388Arg)	GJC2	Uncertain significance	criteria provided, single submitter
3600424	NM_020435.4(GJC2):c.373C>G (p.Arg125Gly)	GJC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3893127	NM_020435.4(GJC2):c.256G>A (p.Val86Ile)	GJC2	Uncertain significance	criteria provided, single submitter
4292042	NM_020435.4(GJC2):c.215C>T (p.Ala72Val)	GJC2	Uncertain significance	criteria provided, single submitter
943603	NM_020435.4(GJC2):c.436_462del (p.Pro146_Glu154del)	GJC2	Uncertain significance	criteria provided, single submitter
235758	NM_020435.4(GJC2):c.108C>T (p.Ile36=)	GJC2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
GJC2	Strong	Autosomal dominant	lymphatic malformation 3	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJC2	Orphanet:280282	Pelizaeus-Merzbacher-like disease due to GJC2 mutation
GJC2	Orphanet:320401	Autosomal recessive spastic paraplegia type 44
GJC2	Orphanet:568051	GJC2-related late-onset primary lymphedema

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
GJC2	HGNC:17494	ENSG00000198835	Q5T442	Gap junction gamma-2 protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJC2	Gap junction gamma-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

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)
GJC2	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS

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
C1 segment of cervical spinal cord	1
inferior vagus X ganglion	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJC2	181	tissue_specific	yes	C1 segment of cervical spinal cord, spinal cord, inferior vagus X ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJC2	638

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJC2	Q5T442	68.50

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
Gap junction assembly	1	292.8×	0.003	GJC2

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
cell communication by electrical coupling	1	4213.0×	7e-04	GJC2
response to toxic substance	1	210.7×	0.007	GJC2
cell-cell signaling	1	69.6×	0.014	GJC2

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
GJC2	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	GJC2

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)
GJC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.