Norum disease

Summary

Norum disease (MONDO:0009515) is a disease caused by LCAT (GenCC Strong), with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include cosyntropin.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LCAT (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 74
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		70	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Norum disease
Mondo ID	MONDO:0009515
OMIM	245900
Orphanet	79293
DOID	DOID:1391
ICD-11	1848131619
NCIT	C84813
SNOMED CT	238091006
UMLS	C0023195
MedGen	9698
GARD	0004011
Is cancer (heuristic)	no

Also known as: complete LCAT deficiency · FLD · lecithin acyltransferase deficiency · lecithin:cholesterol acyltransferase deficiency · Norum disease

Data availability: 74 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › hypolipoproteinemia › Norum disease

Related subtypes (2): Tangier disease, hypobetalipoproteinemia

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

74 retrieved; paginated sample, class counts are floors:

49 uncertain significance, 9 likely pathogenic, 6 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 3 pathogenic, 2 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1454135	NM_000229.2(LCAT):c.837_838del (p.Arg280fs)	LCAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3581207	NM_000229.2(LCAT):c.511C>T (p.Arg171Trp)	LCAT	Pathogenic	criteria provided, single submitter
3581208	NM_000229.2(LCAT):c.496G>A (p.Ala166Thr)	LCAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3660	NM_000229.2(LCAT):c.440C>T (p.Thr147Ile)	LCAT	Pathogenic	criteria provided, multiple submitters, no conflicts
3662	NM_000229.2(LCAT):c.101C>T (p.Pro34Leu)	LCAT	Pathogenic	criteria provided, multiple submitters, no conflicts
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
1338728	NM_000229.2(LCAT):c.802C>T (p.Arg268Cys)	LCAT	Likely pathogenic	criteria provided, single submitter
2585273	NM_000229.2(LCAT):c.428-2A>T	LCAT	Likely pathogenic	criteria provided, single submitter
3581201	NM_000229.2(LCAT):c.799C>T (p.Gln267Ter)	LCAT	Likely pathogenic	criteria provided, single submitter
3581202	NM_000229.2(LCAT):c.794_795del (p.Glu265fs)	LCAT	Likely pathogenic	criteria provided, single submitter
3581209	NM_000229.2(LCAT):c.488_489del (p.Val163fs)	LCAT	Likely pathogenic	criteria provided, single submitter
3581214	NM_000229.2(LCAT):c.254G>A (p.Trp85Ter)	LCAT	Likely pathogenic	criteria provided, single submitter
3581217	NM_000229.2(LCAT):c.142_154+1dup	LCAT	Likely pathogenic	criteria provided, single submitter
3581220	NM_000229.2(LCAT):c.115A>T (p.Lys39Ter)	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
1456665	NM_000229.2(LCAT):c.110C>T (p.Thr37Met)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1769652	NM_000229.2(LCAT):c.1310C>T (p.Pro437Leu)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2447203	NM_000229.2(LCAT):c.580G>A (p.Ala194Thr)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2562382	NM_000229.2(LCAT):c.1020C>T (p.Gly340=)	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
3581216	NM_000229.2(LCAT):c.167T>C (p.Leu56Pro)	LCAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1348002	NM_000229.2(LCAT):c.35C>T (p.Thr12Met)	LCAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1390755	NM_000229.2(LCAT):c.1021G>A (p.Val341Met)	LCAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1426099	NM_000229.2(LCAT):c.1078C>A (p.Pro360Thr)	LCAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1447512	NM_000229.2(LCAT):c.1192G>A (p.Gly398Arg)	LCAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1750055	NM_000229.2(LCAT):c.584A>G (p.Tyr195Cys)	LCAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1764260	NM_000229.2(LCAT):c.867C>A (p.Phe289Leu)	LCAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1765383	NM_000229.2(LCAT):c.899G>A (p.Arg300His)	LCAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1766361	NM_000229.2(LCAT):c.925C>G (p.Leu309Val)	LCAT	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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	Strong	Autosomal recessive	Norum disease	7

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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
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: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LCAT	Enzyme (other)	yes	2.3.1.43	LACT/PDAT_acylTrfase, AB_hydrolase_fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
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
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

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LCAT	P04180	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
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 1 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	8426.0×	0.002	LCAT
lipoprotein biosynthetic process	1	2808.7×	0.002	LCAT
aflatoxin metabolic process	1	2407.4×	0.002	LCAT
very-low-density lipoprotein particle remodeling	1	2106.5×	0.002	LCAT
response to copper ion	1	1532.0×	0.002	LCAT
reverse cholesterol transport	1	936.2×	0.002	LCAT
phosphatidylcholine biosynthetic process	1	802.5×	0.002	LCAT
high-density lipoprotein particle remodeling	1	802.5×	0.002	LCAT
phosphatidylcholine metabolic process	1	802.5×	0.002	LCAT
cholesterol transport	1	732.7×	0.002	LCAT
phospholipid metabolic process	1	343.9×	0.004	LCAT
response to glucocorticoid	1	324.1×	0.004	LCAT
cholesterol metabolic process	1	195.9×	0.006	LCAT
cholesterol homeostasis	1	156.0×	0.007	LCAT
lipid metabolic process	1	91.6×	0.011	LCAT

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
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: 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	1	LCAT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
LCAT	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03368066	PHASE3	COMPLETED	Is Adrenal Insufficiency Under-diagnosed in Hospitalized Cirrhosis Patients?

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
COSYNTROPIN	4	1