hyperlipidemia, familial combined, LPL related

Summary

hyperlipidemia, familial combined, LPL related (MONDO:0007759) is a disease caused by LPL (GenCC Strong), with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include colesevelam and fenofibrate.

At a glance

• Causal gene: LPL (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 63
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperlipidemia, familial combined, LPL related
Mondo ID	MONDO:0007759
OMIM	144250
UMLS	C0020474
MedGen	6965
GARD	0015077
Is cancer (heuristic)	no

Also known as: combined hyperlipidemia, familial · FCHL · hyperlipidemia, familial combined

Data availability: 63 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 › familial hyperlipidemia › hyperlipidemia, familial combined, LPL related

Related subtypes (9): familial hypercholesterolemia, cholesterol-ester transfer protein deficiency, hyperlipoproteinemia type V, familial apolipoprotein C-II deficiency, familial lipoprotein lipase deficiency, hyperlipidemia, combined, 2, hyperlipidemia due to hepatic triglyceride lipase deficiency, 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

63 retrieved; paginated sample, class counts are floors:

13 conflicting classifications of pathogenicity, 13 likely pathogenic, 11 pathogenic/likely pathogenic, 11 uncertain significance, 11 pathogenic, 1 benign/likely benign, 1 benign, 1 benign/likely benign; other, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066635	NM_000237.3(LPL):c.547G>A (p.Asp183Asn)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1203042	NM_000237.3(LPL):c.292G>A (p.Ala98Thr)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1366216	NM_000237.3(LPL):c.688del (p.Val230fs)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1522	NM_000237.3(LPL):c.644G>A (p.Gly215Glu)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1527	NM_000237.3(LPL):c.701C>T (p.Pro234Leu)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1530	NM_000237.3(LPL):c.809G>A (p.Arg270His)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1535	NM_000237.3(LPL):c.249+1G>A	LPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1537	NM_000237.3(LPL):c.1227G>A (p.Trp409Ter)	LPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1539	NM_000237.3(LPL):c.829G>A (p.Asp277Asn)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1540	NM_000237.3(LPL):c.337T>C (p.Trp113Arg)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1541	NM_000237.3(LPL):c.272G>A (p.Trp91Ter)	LPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1543	NM_000237.3(LPL):c.1081G>A (p.Ala361Thr)	LPL	Pathogenic	criteria provided, single submitter
1548	NM_000237.3(LPL):c.808C>T (p.Arg270Cys)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1554	NM_000237.3(LPL):c.755T>C (p.Ile252Thr)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685928	NM_000237.3(LPL):c.88+1G>T	LPL	Pathogenic	criteria provided, single submitter
1685930	NM_000237.3(LPL):c.691G>A (p.Asp231Asn)	LPL	Pathogenic	criteria provided, single submitter
1685932	NM_000237.3(LPL):c.984G>T (p.Met328Ile)	LPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1693264	NM_000237.3(LPL):c.1019-2A>T	LPL	Pathogenic	criteria provided, multiple submitters, no conflicts
3068354	NM_000237.3(LPL):c.1127_1137del (p.Ile376fs)	LPL	Pathogenic	criteria provided, single submitter
3340534	NM_000237.3(LPL):c.827T>C (p.Ile276Thr)	LPL	Pathogenic	criteria provided, single submitter
3595455	NM_000237.3(LPL):c.3G>C (p.Met1Ile)	LPL	Pathogenic	criteria provided, multiple submitters, no conflicts
855588	NM_000237.3(LPL):c.835C>G (p.Leu279Val)	LPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1392632	NM_000237.3(LPL):c.1139+7A>G	LPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685369	NM_000237.3(LPL):c.1306G>C (p.Gly436Arg)	LPL	Likely pathogenic	criteria provided, single submitter
1803250	NM_000237.3(LPL):c.867C>A (p.Tyr289Ter)	LPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3066297	NM_000237.3(LPL):c.386_389del (p.Lys129fs)	LPL	Likely pathogenic	criteria provided, single submitter
3251541	NM_000237.3(LPL):c.802C>T (p.His268Tyr)	LPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595456	NM_000237.3(LPL):c.542-1G>A	LPL	Likely pathogenic	criteria provided, single submitter
3595457	NM_000237.3(LPL):c.663_670dup (p.Gln224fs)	LPL	Likely pathogenic	criteria provided, single submitter
3595458	NM_000237.3(LPL):c.1242C>G (p.Tyr414Ter)	LPL	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
LPL	Strong	Autosomal dominant	hyperlipidemia, familial combined, LPL related	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LPL	Orphanet:309015	Familial lipoprotein 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
LPL	HGNC:6677	ENSG00000175445	P06858	Lipoprotein lipase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LPL	Lipoprotein lipase	Key enzyme in triglyceride metabolism.

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)
LPL	Enzyme (other)	yes	3.1.1.34	TAG_lipase, PLAT/LH2_dom, Lipo_Lipase

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
dorsal root ganglion	1
olfactory bulb	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LPL	272	broad	marker	olfactory bulb, trigeminal ganglion, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LPL	2,149

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LPL	P06858	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. 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 remodeling	1	1142.0×	0.011	LPL
Assembly of active LPL and LIPC lipase complexes	1	601.0×	0.011	LPL
Plasma lipoprotein remodeling	1	475.8×	0.011	LPL
Metabolism of fat-soluble vitamins	1	380.7×	0.011	LPL
Visual phototransduction	1	259.6×	0.011	LPL
Retinoid metabolism and transport	1	248.3×	0.011	LPL
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.011	LPL
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	215.5×	0.011	LPL
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	196.9×	0.011	LPL
Adipogenesis	1	156.4×	0.012	LPL
Epigenetic regulation by WDR5-containing histone modifying complexes	1	154.3×	0.012	LPL
Transcriptional regulation of white adipocyte differentiation	1	129.8×	0.013	LPL
Metabolism of vitamins and cofactors	1	116.5×	0.013	LPL
Sensory Perception	1	95.2×	0.015	LPL
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	82.8×	0.016	LPL
Epigenetic regulation of gene expression	1	71.4×	0.018	LPL
Transport of small molecules	1	25.1×	0.047	LPL
Gene expression (Transcription)	1	17.8×	0.062	LPL
Developmental Biology	1	14.5×	0.073	LPL
Metabolism	1	11.6×	0.086	LPL

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
low-density lipoprotein particle mediated signaling	1	5617.3×	0.002	LPL
chylomicron remodeling	1	4213.0×	0.002	LPL
very-low-density lipoprotein particle clearance	1	3370.4×	0.002	LPL
positive regulation of cholesterol storage	1	2407.4×	0.002	LPL
cellular response to nutrient	1	2106.5×	0.002	LPL
very-low-density lipoprotein particle remodeling	1	2106.5×	0.002	LPL
positive regulation of chemokine (C-X-C motif) ligand 2 production	1	1532.0×	0.002	LPL
positive regulation of lipid storage	1	1404.3×	0.002	LPL
positive regulation of adipose tissue development	1	1053.2×	0.003	LPL
positive regulation of macrophage derived foam cell differentiation	1	842.6×	0.003	LPL
triglyceride catabolic process	1	802.5×	0.003	LPL
high-density lipoprotein particle remodeling	1	802.5×	0.003	LPL
cellular response to fatty acid	1	702.2×	0.003	LPL
retinoid metabolic process	1	495.6×	0.004	LPL
triglyceride homeostasis	1	481.5×	0.004	LPL
triglyceride metabolic process	1	443.5×	0.004	LPL
positive regulation of chemokine production	1	374.5×	0.004	LPL
fatty acid biosynthetic process	1	351.1×	0.004	LPL
phospholipid metabolic process	1	343.9×	0.004	LPL
positive regulation of fat cell differentiation	1	300.9×	0.005	LPL
positive regulation of interleukin-1 beta production	1	259.3×	0.005	LPL
response to glucose	1	255.3×	0.005	LPL
fatty acid metabolic process	1	193.7×	0.006	LPL
response to bacterium	1	193.7×	0.006	LPL
positive regulation of interleukin-6 production	1	166.8×	0.007	LPL
cholesterol homeostasis	1	156.0×	0.007	LPL
positive regulation of tumor necrosis factor production	1	153.2×	0.007	LPL
positive regulation of inflammatory response	1	145.3×	0.007	LPL

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
LPL	ORLISTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LPL	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ORLISTAT	4	LPL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LPL	16	Binding:16

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LPL	3.1.1.34	lipoprotein lipase

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	LPL

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LPL
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: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE4	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00754039	PHASE4	COMPLETED	Study to Compare Welchol and TriCor to TriCor Alone in Patients With High Cholesterol
NCT02035215	PHASE3	UNKNOWN	Phase 3 Study to Evaluate the Efficacy and Safety of Omega-3-acids Ethylesters 90 in Type Ⅱb Hyperlipidemia
NCT00005313	Not specified	COMPLETED	Human Lipoprotein Pathophysiology - Subproject: Genetics of Familial Combined Hyperlipidemia
NCT00005368	Not specified	COMPLETED	Genetic Epidemiology of Hypertriglyceridemia
NCT00064688	Not specified	WITHDRAWN	Genomic Dissection of a QTL Affecting the Lipid Profile
NCT00365235	Not specified	COMPLETED	Understanding the Genetic Basis of Familial Combined Hyperlipidemia in Mexican Individuals

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
COLESEVELAM	4	1
FENOFIBRATE	4	1
CHEMBL1201677	0	1