amelogenesis imperfecta type 1A

Summary

amelogenesis imperfecta type 1A (MONDO:0007094) is a disease caused by LAMB3 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: LAMB3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 116

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amelogenesis imperfecta type 1A
Mondo ID	MONDO:0007094
MeSH	C538240
OMIM	104530
DOID	DOID:0110054
UMLS	C4011403
MedGen	859840
GARD	0015038
Is cancer (heuristic)	no

Also known as: AI1A · amelogenesis imperfecta caused by mutation in LAMB3 · amelogenesis imperfecta local hypoplastic · amelogenesis imperfecta, type IA · LAMB3 amelogenesis imperfecta · local hypoplastic amelogenesis imperfecta

Data availability: 116 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 › amelogenesis imperfecta › amelogenesis imperfecta type 1 › amelogenesis imperfecta type 1A

Related subtypes (5): amelogenesis imperfecta type 1B, amelogenesis imperfecta type 1C, amelogenesis imperfecta type 1H, amelogenesis imperfecta type 1F, amelogenesis imperfecta, type 1J

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

116 retrieved; paginated sample, class counts are floors:

29 likely pathogenic, 25 pathogenic, 23 benign, 17 uncertain significance, 17 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2211005	NM_000494.4(COL17A1):c.340del (p.Ser114fs)	COL17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572029	NM_000494.4(COL17A1):c.3297C>A (p.Tyr1099Ter)	COL17A1	Pathogenic	no assertion criteria provided
2572031	NM_000494.4(COL17A1):c.3456del (p.Pro1154fs)	COL17A1	Pathogenic	criteria provided, single submitter
2572032	NM_000494.4(COL17A1):c.3462_3463del (p.Gly1155fs)	COL17A1	Pathogenic	no assertion criteria provided
2572035	NM_000494.4(COL17A1):c.4147_4148del (p.Ser1383fs)	COL17A1	Pathogenic	no assertion criteria provided
2572036	NM_000494.4(COL17A1):c.541_550del (p.Asn181fs)	COL17A1	Pathogenic	no assertion criteria provided
2572040	NM_000494.4(COL17A1):c.2912del (p.Pro971fs)	COL17A1	Pathogenic	no assertion criteria provided
931124	NM_000494.4(COL17A1):c.460C>T (p.Arg154Ter)	COL17A1	Pathogenic	criteria provided, single submitter
1074943	NM_000228.3(LAMB3):c.1676del (p.Gly558_Leu559insTer)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361158	NM_000228.3(LAMB3):c.435_436del (p.Tyr146fs)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14539	NM_000228.3(LAMB3):c.1903C>T (p.Arg635Ter)	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
14541	NM_000228.3(LAMB3):c.124C>T (p.Arg42Ter)	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
14543	NM_000228.3(LAMB3):c.628G>A (p.Glu210Lys)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14548	NM_000228.3(LAMB3):c.1587_1588del (p.Gly530fs)	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
155999	NM_000228.3(LAMB3):c.1133-22G>A	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
180676	NM_000228.3(LAMB3):c.3431C>A (p.Ser1144Ter)	LAMB3	Pathogenic	no assertion criteria provided
180677	NM_000228.3(LAMB3):c.3394dup (p.Glu1132fs)	LAMB3	Pathogenic	no assertion criteria provided
188764	NM_000228.3(LAMB3):c.1705C>T (p.Arg569Ter)	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
188937	NM_000228.3(LAMB3):c.463dup (p.Ser155fs)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189004	NM_000228.3(LAMB3):c.1365_1366del (p.Asn456fs)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189034	NM_000228.3(LAMB3):c.1978C>T (p.Arg660Ter)	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
2095236	NM_000228.3(LAMB3):c.2242G>T (p.Glu748Ter)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2106326	NM_000228.3(LAMB3):c.2495del (p.Ala832fs)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2420300	NM_000228.3(LAMB3):c.2116del (p.Lys705_Ile706insTer)	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
265229	NM_000228.3(LAMB3):c.1132+5G>A	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2696593	NM_000228.3(LAMB3):c.1357del (p.Cys453fs)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734071	NM_000228.3(LAMB3):c.3190_3191delinsTA (p.Ala1064Ter)	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
2910131	NM_000228.3(LAMB3):c.3163del (p.Ala1055fs)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
295145	NM_000228.3(LAMB3):c.225_226del (p.His75fs)	LAMB3	Pathogenic	criteria provided, multiple submitters, no conflicts
35480	NM_000228.3(LAMB3):c.727C>T (p.Gln243Ter)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 7 · 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
LAMB3	Strong	Autosomal dominant	amelogenesis imperfecta type 1A	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAMB3	Orphanet:100031	Hypoplastic amelogenesis imperfecta
LAMB3	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
LAMB3	Orphanet:79404	Severe generalized junctional epidermolysis bullosa
COL17A1	Orphanet:251393	Localized junctional epidermolysis bullosa
COL17A1	Orphanet:293381	Epithelial recurrent erosion dystrophy
COL17A1	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
COL17A1	Orphanet:79406	Late-onset junctional epidermolysis bullosa

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
LAMB3	HGNC:6490	ENSG00000196878	Q13751	Laminin subunit beta-3	gencc,clinvar
COL17A1	HGNC:2194	ENSG00000065618	Q9UMD9	Collagen alpha-1(XVII) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LAMB3	Laminin subunit beta-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.
COL17A1	Collagen alpha-1(XVII) chain	May play a role in the integrity of hemidesmosome and the attachment of basal keratinocytes to the underlying basement membrane.

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)
LAMB3	Other/Unknown	no		EGF, LE_dom, Laminin_N
COL17A1	Other/Unknown	no		Collagen, Collagen_superfamily

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
cartilage tissue	1
gingival epithelium	1
periodontal ligament	1
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LAMB3	215	ubiquitous	marker	cartilage tissue, periodontal ligament, gingival epithelium
COL17A1	182	broad	marker	skin of abdomen, skin of leg, zone of skin

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL17A1	1,769
LAMB3	1,697

Intra-cohort edges

A	B	Sources
COL17A1	LAMB3	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL17A1	Q9UMD9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LAMB3	Q13751	78.55

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
Type I hemidesmosome assembly	2	1038.2×	2e-05	LAMB3, COL17A1
Assembly of collagen fibrils and other multimeric structures	2	200.3×	3e-04	LAMB3, COL17A1
Anchoring fibril formation	1	380.7×	0.014	LAMB3
MET promotes cell motility	1	300.5×	0.014	LAMB3
Attachment of bacteria to epithelial cells	1	248.3×	0.014	LAMB3
Collagen formation	1	228.4×	0.014	LAMB3
Laminin interactions	1	190.3×	0.014	LAMB3
MET activates PTK2 signaling	1	190.3×	0.014	LAMB3
Signaling by MET	1	158.6×	0.014	LAMB3
Formation of the dystrophin-glycoprotein complex (DGC)	1	154.3×	0.014	LAMB3
Collagen chain trimerization	1	129.8×	0.015	COL17A1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.016	LAMB3
Cell junction organization	1	93.6×	0.017	LAMB3
Collagen degradation	1	87.8×	0.017	COL17A1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.017	COL17A1
Non-integrin membrane-ECM interactions	1	77.2×	0.018	LAMB3
Cell-Cell communication	1	68.8×	0.019	LAMB3
Degradation of the extracellular matrix	1	58.9×	0.021	LAMB3
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.026	COL17A1
Extracellular matrix organization	1	31.6×	0.035	LAMB3
Signaling by Receptor Tyrosine Kinases	1	25.8×	0.040	LAMB3
Signal Transduction	1	5.1×	0.187	LAMB3

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
epidermis development	2	210.7×	1e-04	LAMB3, COL17A1
hemidesmosome assembly	1	1203.7×	0.002	COL17A1
endodermal cell differentiation	1	247.8×	0.007	LAMB3
brown fat cell differentiation	1	216.1×	0.007	LAMB3
cell-matrix adhesion	1	81.8×	0.015	COL17A1
cell adhesion	1	18.7×	0.053	LAMB3

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
LAMB3	0	0
COL17A1	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	LAMB3, COL17A1

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)
LAMB3	0	—
COL17A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.