epidermolysis bullosa, junctional 2A, intermediate

Summary

epidermolysis bullosa, junctional 2A, intermediate (MONDO:0030746) is a disease caused by LAMA3 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: LAMA3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 64

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolysis bullosa, junctional 2A, intermediate
Mondo ID	MONDO:0030746
OMIM	619783
UMLS	C5676936
MedGen	1807376
GARD	0025629
Is cancer (heuristic)	no

Also known as: epidermolysis bullosa, junctional 2A, generalised intermediate · epidermolysis bullosa, junctional 2A, generalized intermediate · epidermolysis bullosa, junctional 2A, intermediate · epidermolysis bullosa, junctional 2A, non-herlitz IIA · JEB2A

Data availability: 64 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › vesiculobullous skin disease › epidermolysis bullosa › inherited epidermolysis bullosa › junctional epidermolysis bullosa › epidermolysis bullosa, junctional 2A, intermediate

Related subtypes (14): late-onset localized junctional epidermolysis bullosa-intellectual disability syndrome, junctional epidermolysis bullosa, non-Herlitz type, junctional epidermolysis bullosa Herlitz type, junctional epidermolysis bullosa with pyloric atresia, laryngo-onycho-cutaneous syndrome, epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, junctional epidermolysis bullosa inversa, late-onset junctional epidermolysis bullosa, epidermolysis bullosa, junctional 2B, severe, epidermolysis bullosa, junctional 3A, intermediate, epidermolysis bullosa, junctional 3B, severe, epidermolysis bullosa, junctional 4, intermediate, epidermolysis bullosa, junctional 5A, intermediate, epidermolysis bullosa, junctional 6, with pyloric atresia

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

64 retrieved; paginated sample, class counts are floors:

25 likely pathogenic, 18 uncertain significance, 8 pathogenic/likely pathogenic, 7 pathogenic, 5 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069385	NM_198129.4(LAMA3):c.5546del (p.Gly1849fs)	LAMA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321416	NM_198129.4(LAMA3):c.7204C>T (p.Arg2402Ter)	LAMA3	Pathogenic	criteria provided, multiple submitters, no conflicts
1382563	NM_198129.4(LAMA3):c.8705del (p.Gln2902fs)	LAMA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699949	LAMA3, ARG1331CYS	LAMA3	Pathogenic	no assertion criteria provided
1699950	LAMA3, IVS35, +1, G-A	LAMA3	Pathogenic	no assertion criteria provided
1802262	NM_198129.4(LAMA3):c.5121del (p.Gln1707fs)	LAMA3	Pathogenic	criteria provided, single submitter
1958581	NM_000227.6(LAMA3):c.139C>T (p.Gln47Ter)	LAMA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2820486	NM_198129.4(LAMA3):c.8420T>G (p.Leu2807Ter)	LAMA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2899213	NM_198129.4(LAMA3):c.8211C>A (p.Cys2737Ter)	LAMA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3039514	NM_198129.4(LAMA3):c.1273+51C>T	LAMA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239675	NM_198129.4(LAMA3):c.1273+26_1273+41del	LAMA3	Pathogenic	criteria provided, single submitter
3583199	NM_198129.4(LAMA3):c.8043G>A (p.Ser2681=)	LAMA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370752	NM_198129.4(LAMA3):c.5049del (p.Cys1684fs)	LAMA3	Pathogenic	criteria provided, multiple submitters, no conflicts
8792	NM_198129.4(LAMA3):c.6808C>T (p.Arg2270Ter)	LAMA3	Pathogenic	criteria provided, multiple submitters, no conflicts
952726	NM_198129.4(LAMA3):c.8599C>T (p.Gln2867Ter)	LAMA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441682	NM_198129.4(LAMA3):c.6319-1G>A	LAMA3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3234987	NM_198129.4(LAMA3):c.6412del (p.Val2139fs)	LAMA3	Likely pathogenic	criteria provided, single submitter
3381858	NM_198129.4(LAMA3):c.1789-1G>C	LAMA3	Likely pathogenic	criteria provided, single submitter
3583191	NM_198129.4(LAMA3):c.5462-2A>G	LAMA3	Likely pathogenic	criteria provided, single submitter
3583192	NM_198129.4(LAMA3):c.5837-1G>A	LAMA3	Likely pathogenic	criteria provided, single submitter
3583193	NM_198129.4(LAMA3):c.5910G>A (p.Trp1970Ter)	LAMA3	Likely pathogenic	criteria provided, single submitter
3583194	NM_198129.4(LAMA3):c.5973del (p.Ala1992fs)	LAMA3	Likely pathogenic	criteria provided, single submitter
3583195	NM_198129.4(LAMA3):c.6005T>A (p.Leu2002Ter)	LAMA3	Likely pathogenic	criteria provided, single submitter
3583196	NM_198129.4(LAMA3):c.6202-2A>G	LAMA3	Likely pathogenic	criteria provided, single submitter
3583198	NM_198129.4(LAMA3):c.7289del (p.Gly2430fs)	LAMA3	Likely pathogenic	criteria provided, single submitter
3583200	NM_198129.4(LAMA3):c.8044-2A>C	LAMA3	Likely pathogenic	criteria provided, single submitter
3583201	NM_198129.4(LAMA3):c.8177+2T>A	LAMA3	Likely pathogenic	criteria provided, single submitter
3583202	NM_198129.4(LAMA3):c.8577-2A>G	LAMA3	Likely pathogenic	criteria provided, single submitter
3583204	NM_198129.4(LAMA3):c.9498del (p.His3167fs)	LAMA3	Likely pathogenic	criteria provided, single submitter
3583205	NM_198129.4(LAMA3):c.9500dup (p.His3167fs)	LAMA3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 4 · 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
LAMA3	Definitive	Autosomal recessive	junctional epidermolysis bullosa	13
LAMA4	Definitive	Autosomal recessive	junctional epidermolysis bullosa	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAMA3	Orphanet:2407	Laryngo-onycho-cutaneous syndrome
LAMA3	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
LAMA3	Orphanet:79404	Severe generalized junctional epidermolysis bullosa
LAMA4	Orphanet:154	Familial isolated dilated cardiomyopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LAMA3	HGNC:6483	ENSG00000053747	Q16787	Laminin subunit alpha-3	gencc,clinvar
LAMA4	HGNC:6484	ENSG00000112769	Q16363	Laminin subunit alpha-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LAMA3	Laminin subunit alpha-3	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
LAMA4	Laminin subunit alpha-4	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

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)
LAMA3	Other/Unknown	no		Laminin_IV, EGF, Laminin_G
LAMA4	Other/Unknown	no		EGF, Laminin_G, LE_dom

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 lung	1
skin of abdomen	1
skin of leg	1
lower esophagus	1
lower esophagus muscularis layer	1
nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LAMA3	239	broad	marker	right lung, skin of leg, skin of abdomen
LAMA4	268	ubiquitous	marker	lower esophagus muscularis layer, lower esophagus, nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LAMA4	2,688
LAMA3	2,195

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LAMA4	Q16363	73.75
LAMA3	Q16787

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MET promotes cell motility	2	601.0×	3e-05	LAMA3, LAMA4
Attachment of bacteria to epithelial cells	2	496.5×	3e-05	LAMA3, LAMA4
Laminin interactions	2	380.7×	3e-05	LAMA3, LAMA4
MET activates PTK2 signaling	2	380.7×	3e-05	LAMA3, LAMA4
Signaling by MET	2	317.2×	3e-05	LAMA3, LAMA4
Formation of the dystrophin-glycoprotein complex (DGC)	2	308.6×	3e-05	LAMA3, LAMA4
Developmental Lineage of Pancreatic Ductal Cells	2	228.4×	5e-05	LAMA3, LAMA4
Non-integrin membrane-ECM interactions	2	154.3×	9e-05	LAMA3, LAMA4
ECM proteoglycans	2	150.3×	9e-05	LAMA3, LAMA4
Extracellular matrix organization	2	63.1×	5e-04	LAMA3, LAMA4
Signaling by Receptor Tyrosine Kinases	2	51.7×	6e-04	LAMA3, LAMA4
Type I hemidesmosome assembly	1	519.1×	0.003	LAMA3
Anchoring fibril formation	1	380.7×	0.004	LAMA3
Collagen formation	1	228.4×	0.006	LAMA3
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.012	LAMA3
Signal Transduction	2	10.2×	0.012	LAMA3, LAMA4
Cell junction organization	1	93.6×	0.012	LAMA3
Cell-Cell communication	1	68.8×	0.015	LAMA3
Degradation of the extracellular matrix	1	58.9×	0.017	LAMA3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of embryonic development	2	330.4×	5e-05	LAMA3, LAMA4
regulation of cell adhesion	2	306.4×	5e-05	LAMA3, LAMA4
regulation of cell migration	2	157.5×	1e-04	LAMA3, LAMA4
hemidesmosome assembly	1	1203.7×	0.002	LAMA3
endodermal cell differentiation	1	247.8×	0.007	LAMA3
negative regulation of cold-induced thermogenesis	1	172.0×	0.009	LAMA4
epidermis development	1	105.3×	0.012	LAMA3
cell-cell adhesion	1	50.8×	0.022	LAMA3
cell adhesion	1	18.7×	0.053	LAMA4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
LAMA3	0	0
LAMA4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	LAMA3, LAMA4

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)
LAMA3	0	—
LAMA4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.