Hyperlipidemia due to hepatic triglyceride lipase deficiency

Summary

Hyperlipidemia due to hepatic triglyceride lipase deficiency (MONDO:0013533) is a disease caused by LIPC (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: LIPC (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 67
• Phenotypes (HPO): 5

Clinical features

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0002155	Hypertriglyceridemia	Obligate (100%)
HP:0012184	Increased HDL cholesterol concentration	Obligate (100%)
HP:0001013	Eruptive xanthomas	Very frequent (80-99%)
HP:0001681	Angina pectoris	Frequent (30-79%)
HP:0005181	Premature coronary artery atherosclerosis	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperlipidemia due to hepatic triglyceride lipase deficiency
Mondo ID	MONDO:0013533
OMIM	614025
Orphanet	140905
SNOMED CT	720940008
UMLS	C3151466
MedGen	462816
GARD	0012864
Is cancer (heuristic)	no

Also known as: hyperlipidemia due to hepatic lipase deficiency · hyperlipidemia due to HL deficiency · hyperlipidemia due to HTGL deficiency

Data availability: 67 ClinVar variants · 4 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 › familial hyperlipidemia › hyperlipidemia due to hepatic triglyceride lipase deficiency

Related subtypes (9): familial hypercholesterolemia, cholesterol-ester transfer protein deficiency, hyperlipidemia, familial combined, LPL related, hyperlipoproteinemia type V, familial apolipoprotein C-II deficiency, familial lipoprotein lipase deficiency, hyperlipidemia, combined, 2, hyperlipoproteinemia, type 1D, hyperlipoproteinemia type 3

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

67 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 11 conflicting classifications of pathogenicity, 10 benign/likely benign, 9 benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1174131	NM_000236.3(LIPC):c.1068= (p.Phe356=)	LIPC	Pathogenic	no assertion criteria provided
29776	NM_000236.3(LIPC):c.583G>A (p.Ala195Thr)	LIPC	Pathogenic	no assertion criteria provided
1337611	NM_000236.3(LIPC):c.89-4G>A	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14451	NM_000236.3(LIPC):c.1214C>T (p.Thr405Met)	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14452	NM_000236.3(LIPC):c.866C>T (p.Ser289Phe)	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2584633	NM_000236.3(LIPC):c.88+8C>A	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316663	NM_000236.3(LIPC):c.588G>A (p.Ala196=)	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316676	NM_000236.3(LIPC):c.1203C>T (p.Ser401=)	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
735412	NM_000236.3(LIPC):c.1226A>C (p.Asp409Ala)	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885174	NM_000236.3(LIPC):c.1388+13T>G	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885175	NM_000236.3(LIPC):c.1415A>T (p.Asp472Val)	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886947	NM_000236.3(LIPC):c.67C>T (p.Leu23Phe)	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886950	NM_000236.3(LIPC):c.207G>A (p.Pro69=)	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1498752	NM_000236.3(LIPC):c.1330C>T (p.Arg444Cys)	LIPC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1678437	NM_000236.3(LIPC):c.674G>A (p.Arg225Gln)	LIPC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2085301	NM_000236.3(LIPC):c.456+2T>C	LIPC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2489894	NM_000236.3(LIPC):c.1271_1275del (p.Ala424fs)	LIPC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2502204	NM_000236.3(LIPC):c.1024G>A (p.Val342Ile)	LIPC	Uncertain significance	criteria provided, single submitter
2502224	NM_000236.3(LIPC):c.377C>A (p.Ala126Asp)	LIPC	Uncertain significance	criteria provided, single submitter
2502235	NM_000236.3(LIPC):c.353G>A (p.Gly118Glu)	LIPC	Uncertain significance	criteria provided, single submitter
2502241	NM_000236.3(LIPC):c.1031G>A (p.Arg344Gln)	LIPC	Uncertain significance	criteria provided, single submitter
316654	NM_000236.3(LIPC):c.206C>T (p.Pro69Leu)	LIPC	Uncertain significance	criteria provided, multiple submitters, no conflicts
316657	NM_000236.3(LIPC):c.316G>A (p.Ala106Thr)	LIPC	Uncertain significance	criteria provided, single submitter
316658	NM_000236.3(LIPC):c.317C>T (p.Ala106Val)	LIPC	Uncertain significance	criteria provided, multiple submitters, no conflicts
316659	NM_000236.3(LIPC):c.461C>A (p.Ser154Tyr)	LIPC	Uncertain significance	criteria provided, single submitter
316662	NM_000236.3(LIPC):c.575-5A>G	LIPC	Uncertain significance	criteria provided, single submitter
316667	NM_000236.3(LIPC):c.739G>A (p.Gly247Arg)	LIPC	Uncertain significance	criteria provided, multiple submitters, no conflicts
316669	NM_000236.3(LIPC):c.998G>A (p.Arg333Gln)	LIPC	Uncertain significance	criteria provided, multiple submitters, no conflicts
316675	NM_000236.3(LIPC):c.1169+11G>A	LIPC	Uncertain significance	criteria provided, single submitter
316677	NM_000236.3(LIPC):c.1231G>A (p.Gly411Ser)	LIPC	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
LIPC	Strong	Autosomal recessive	hyperlipidemia due to hepatic triglyceride lipase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LIPC	Orphanet:140905	Hyperlipidemia due to hepatic triacylglycerol lipase 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
LIPC	HGNC:6619	ENSG00000166035	P11150	Hepatic triacylglycerol lipase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LIPC	Hepatic triacylglycerol lipase	Catalyzes the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins, including chylomicrons, intermediate density lipoproteins (IDL), low density lipoproteins (LDL) of large size and high density lipoprot…

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)
LIPC	Other/Unknown	no		TAG_lipase, PLAT/LH2_dom, Lipase_hep

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
colonic epithelium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LIPC	158	broad	marker	right lobe of liver, liver, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LIPC	1,603

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LIPC	P11150	82.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Chylomicron clearance	1	2284.0×	0.003	LIPC
Assembly of active LPL and LIPC lipase complexes	1	601.0×	0.003	LIPC
Plasma lipoprotein remodeling	1	475.8×	0.003	LIPC
Plasma lipoprotein clearance	1	475.8×	0.003	LIPC
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.005	LIPC
Transport of small molecules	1	25.1×	0.040	LIPC

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
intermediate-density lipoprotein particle remodeling	1	16852.0×	7e-04	LIPC
chylomicron remnant clearance	1	2808.7×	0.002	LIPC
very-low-density lipoprotein particle remodeling	1	2106.5×	0.002	LIPC
phosphatidylcholine catabolic process	1	1296.3×	0.002	LIPC
low-density lipoprotein particle remodeling	1	1053.2×	0.002	LIPC
reverse cholesterol transport	1	936.2×	0.002	LIPC
triglyceride catabolic process	1	802.5×	0.002	LIPC
high-density lipoprotein particle remodeling	1	802.5×	0.002	LIPC
triglyceride homeostasis	1	481.5×	0.003	LIPC
fatty acid biosynthetic process	1	351.1×	0.003	LIPC
cholesterol metabolic process	1	195.9×	0.006	LIPC
cholesterol homeostasis	1	156.0×	0.006	LIPC

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
LIPC	ORLISTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LIPC	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ORLISTAT	4	LIPC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LIPC	12	Binding:11, ADMET:1

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
ORLISTAT	4	LIPC

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LIPC
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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.