LCAT deficiency

Summary

LCAT deficiency (MONDO:0018999) is a disease caused by LCAT (GenCC Definitive), with 2 cohort genes and 3 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LCAT (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 38
• Phenotypes (HPO): 13
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		125	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0002155	Hypertriglyceridemia	Very frequent (80-99%)
HP:0003233	Decreased HDL cholesterol concentration	Very frequent (80-99%)
HP:0031799	Decreased apolipoprotein AI level	Very frequent (80-99%)
HP:0000083	Renal insufficiency	Frequent (30-79%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0001878	Hemolytic anemia	Frequent (30-79%)
HP:0002621	Atherosclerosis	Frequent (30-79%)
HP:0007957	Corneal opacity	Frequent (30-79%)
HP:0012213	Decreased glomerular filtration rate	Frequent (30-79%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0003774	Stage 5 chronic kidney disease	Occasional (5-29%)
HP:0005181	Premature coronary artery atherosclerosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	LCAT deficiency
Mondo ID	MONDO:0018999
Orphanet	650
SNOMED CT	49227001
UMLS	C5779633
MedGen	1830326
GARD	0016539
Is cancer (heuristic)	no

Also known as: lecithin-cholesterol acyltransferase deficiency

Data availability: 38 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › hypoalphalipoproteinemia › LCAT deficiency

Related subtypes (5): Tangier disease, combined ApoA-I and ApoC-III deficiency, apolipoprotein A-I deficiency, familial apolipoprotein gene cluster deletion syndrome, apolipoprotein A-II deficiency

Subtypes (2): fish eye disease, Norum disease

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

38 retrieved; paginated sample, class counts are floors:

12 conflicting classifications of pathogenicity, 11 pathogenic, 8 uncertain significance, 2 likely pathogenic, 2 pathogenic/likely pathogenic, 2 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3667	NM_000229.1(LCAT):c.[349G>A;544C>T]		Pathogenic	no assertion criteria provided
3656	NM_000229.2(LCAT):c.508T>C (p.Trp170Arg)	LCAT	Pathogenic	no assertion criteria provided
3657	NM_000229.2(LCAT):c.951G>A (p.Met317Ile)	LCAT	Pathogenic	no assertion criteria provided
3658	NM_000229.2(LCAT):c.491_493dup (p.Arg164_Ala165insGly)	LCAT	Pathogenic	no assertion criteria provided
3659	NM_000229.2(LCAT):c.756C>A (p.Asn252Lys)	LCAT	Pathogenic	no assertion criteria provided
3661	NM_000229.2(LCAT):c.101dup (p.His35fs)	LCAT	Pathogenic	criteria provided, multiple submitters, no conflicts
3665	NM_000229.2(LCAT):c.827T>A (p.Met276Lys)	LCAT	Pathogenic	no assertion criteria provided
3666	NM_000229.2(LCAT):c.698T>C (p.Leu233Pro)	LCAT	Pathogenic	no assertion criteria provided
3669	NM_000229.2(LCAT):c.1197dup (p.Gln400fs)	LCAT	Pathogenic	no assertion criteria provided
3670	NM_000229.2(LCAT):c.1034C>T (p.Thr345Met)	LCAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3671	NM_000229.2(LCAT):c.321C>A (p.Tyr107Ter)	LCAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
626357	NM_000229.2(LCAT):c.997G>A (p.Val333Met)	LCAT	Pathogenic	criteria provided, single submitter
626358	NM_000229.2(LCAT):c.1210A>G (p.Met404Val)	LCAT	Pathogenic	criteria provided, single submitter
3668	NM_000229.2(LCAT):c.475C>T (p.Arg159Trp)	LCAT	Likely pathogenic	criteria provided, single submitter
632262	NM_000229.2(LCAT):c.367C>T (p.Arg123Cys)	LCAT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
320198	NM_000229.2(LCAT):c.981A>C (p.Gly327=)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320199	NM_000229.2(LCAT):c.748+13C>G	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320201	NM_000229.2(LCAT):c.159C>T (p.Pro53=)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3251283	NM_000229.2(LCAT):c.493G>A (p.Ala165Thr)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884652	NM_000229.2(LCAT):c.861C>T (p.His287=)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884654	NM_000229.2(LCAT):c.618C>T (p.Leu206=)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884655	NM_000229.2(LCAT):c.597C>T (p.Val199=)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884656	NM_000229.2(LCAT):c.552C>T (p.Leu184=)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884657	NM_000229.2(LCAT):c.495C>T (p.Ala165=)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885594	NM_000229.2(LCAT):c.465T>C (p.Asn155=)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887804	NM_000229.2(LCAT):c.1173G>A (p.Val391=)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887806	NM_000229.2(LCAT):c.1113G>A (p.Thr371=)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779592	NM_001170700.3(DTHD1):c.1219-2A>T	DTHD1	Uncertain significance	criteria provided, single submitter
320200	NM_000229.2(LCAT):c.534G>T (p.Glu178Asp)	LCAT	Uncertain significance	criteria provided, single submitter
885592	NM_000229.2(LCAT):c.481G>A (p.Glu161Lys)	LCAT	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
LCAT	Definitive	Autosomal recessive	LCAT deficiency	7
DTHD1	Limited	Autosomal recessive	LCAT deficiency

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LCAT	Orphanet:79292	Fish-eye disease
LCAT	Orphanet:79293	Familial LCAT deficiency

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
DTHD1	HGNC:37261	ENSG00000197057	Q6ZMT9	Death domain-containing protein 1	gencc,clinvar
LCAT	HGNC:6522	ENSG00000213398	P04180	Phosphatidylcholine-sterol acyltransferase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LCAT	Phosphatidylcholine-sterol acyltransferase	Central enzyme in the extracellular metabolism of plasma lipoproteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DTHD1	Other/Unknown	no		Death_dom, ZU5_dom, DEATH-like_dom_sf
LCAT	Enzyme (other)	yes	2.3.1.43	LACT/PDAT_acylTrfase, AB_hydrolase_fold

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
bronchial epithelial cell	1
olfactory segment of nasal mucosa	1
right uterine tube	1
right hemisphere of cerebellum	1
right lobe of liver	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DTHD1	128	tissue_specific	marker	right uterine tube, olfactory segment of nasal mucosa, bronchial epithelial cell
LCAT	194	broad	marker	right lobe of liver, right hemisphere of cerebellum, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LCAT	1,609
DTHD1	542

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LCAT	P04180	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DTHD1	Q6ZMT9	69.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
HDL remodeling	1	1142.0×	0.004	LCAT
Plasma lipoprotein remodeling	1	475.8×	0.004	LCAT
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.006	LCAT
Transport of small molecules	1	25.1×	0.040	LCAT

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 high-density lipoprotein particle assembly	1	4213.0×	0.004	LCAT
lipoprotein biosynthetic process	1	1404.3×	0.004	LCAT
aflatoxin metabolic process	1	1203.7×	0.004	LCAT
very-low-density lipoprotein particle remodeling	1	1053.2×	0.004	LCAT
response to copper ion	1	766.0×	0.004	LCAT
reverse cholesterol transport	1	468.1×	0.004	LCAT
phosphatidylcholine biosynthetic process	1	401.2×	0.004	LCAT
high-density lipoprotein particle remodeling	1	401.2×	0.004	LCAT
phosphatidylcholine metabolic process	1	401.2×	0.004	LCAT
cholesterol transport	1	366.4×	0.004	LCAT
phospholipid metabolic process	1	172.0×	0.008	LCAT
response to glucocorticoid	1	162.0×	0.008	LCAT
cholesterol metabolic process	1	98.0×	0.013	LCAT
cholesterol homeostasis	1	78.0×	0.015	LCAT
lipid metabolic process	1	45.8×	0.023	LCAT
signal transduction	1	8.0×	0.121	DTHD1

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
DTHD1	0	0
LCAT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LCAT	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LCAT	2.3.1.43	phosphatidylcholine-sterol O-acyltransferase

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	1	LCAT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DTHD1

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)
DTHD1	0	—
LCAT	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06217588	Not specified	RECRUITING	LCAT (Lecithin Cholesterol Acyl Transferase) Natural History Study
NCT01782027	Not specified	TERMINATED	Mendelian Reverse Cholesterol Transport Study
NCT04737720	Not specified	COMPLETED	Intravenous ACP-501 for Familial LCAT Deficiency (rhLCAT)