hyperlipoproteinemia, type 1D

Summary

hyperlipoproteinemia, type 1D (MONDO:0014412) is a disease caused by GPIHBP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GPIHBP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperlipoproteinemia, type 1D
Mondo ID	MONDO:0014412
OMIM	615947
Orphanet	535458
DOID	DOID:0111420
UMLS	C4014767
MedGen	863204
GARD	0017973
Is cancer (heuristic)	no

Also known as: familial hyperlipidemia caused by mutation in GPIHBP1 · GPIHBP1 familial hyperlipidemia · hyperlipoproteinemia, type 1D

Data availability: 26 ClinVar variants · 5 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 › hyperlipoproteinemia, type 1D

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, hyperlipidemia due to hepatic triglyceride lipase deficiency, 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

26 retrieved; paginated sample, class counts are floors:

9 pathogenic, 6 likely pathogenic, 5 uncertain significance, 3 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031306	NM_178172.6(GPIHBP1):c.323C>G (p.Thr108Arg)	GPIHBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
144013	NM_178172.6(GPIHBP1):c.344A>C (p.Gln115Pro)	GPIHBP1	Pathogenic	no assertion criteria provided
144014	NM_178172.6(GPIHBP1):c.194G>C (p.Cys65Ser)	GPIHBP1	Pathogenic	no assertion criteria provided
144015	NM_178172.6(GPIHBP1):c.202T>G (p.Cys68Gly)	GPIHBP1	Pathogenic	no assertion criteria provided
144017	NM_178172.6(GPIHBP1):c.266G>T (p.Cys89Phe)	GPIHBP1	Pathogenic	no assertion criteria provided
144018	NM_178172.6(GPIHBP1):c.331A>C (p.Thr111Pro)	GPIHBP1	Pathogenic	criteria provided, single submitter
144019	NM_178172.6(GPIHBP1):c.417_433del (p.Pro140fs)	GPIHBP1	Pathogenic	criteria provided, single submitter
144020	NM_178172.6(GPIHBP1):c.194G>A (p.Cys65Tyr)	GPIHBP1	Pathogenic	criteria provided, single submitter
144022	NC_000008.11:g.(?143213218)(143217170_?)del	GPIHBP1	Pathogenic	no assertion criteria provided
1685860	NM_178172.6(GPIHBP1):c.182-1G>T	GPIHBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1687542	NM_178172.6(GPIHBP1):c.193T>C (p.Cys65Arg)	GPIHBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3358985	NM_178172.6(GPIHBP1):c.52+2T>C	GPIHBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
144021	NM_178172.6(GPIHBP1):c.320C>G (p.Ser107Cys)	GPIHBP1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803904	NM_178172.6(GPIHBP1):c.397del (p.Ser133fs)	GPIHBP1	Likely pathogenic	criteria provided, single submitter
3391055	NM_178172.6(GPIHBP1):c.299C>G (p.Ser100Ter)	GPIHBP1	Likely pathogenic	criteria provided, single submitter
4292487	NM_178172.6(GPIHBP1):c.381del (p.Thr127_Met128insTer)	GPIHBP1	Likely pathogenic	criteria provided, single submitter
917845	NM_178172.6(GPIHBP1):c.230G>A (p.Cys77Tyr)	GPIHBP1	Likely pathogenic	no assertion criteria provided
975917	NM_178172.6(GPIHBP1):c.422G>A (p.Trp141Ter)	GPIHBP1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1207087	NM_178172.6(GPIHBP1):c.368G>A (p.Gly123Glu)	GPIHBP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
144016	NM_178172.6(GPIHBP1):c.523G>C (p.Gly175Arg)	GPIHBP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1517312	NM_178172.6(GPIHBP1):c.433C>T (p.Arg145Ter)	GPIHBP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1705446	NM_178172.6(GPIHBP1):c.272C>A (p.Thr91Asn)	GPIHBP1	Uncertain significance	criteria provided, single submitter
1705537	NM_178172.6(GPIHBP1):c.406T>G (p.Cys136Gly)	GPIHBP1	Uncertain significance	criteria provided, single submitter
1783091	NM_178172.6(GPIHBP1):c.106G>C (p.Asp36His)	GPIHBP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2998052	NM_178172.6(GPIHBP1):c.280G>C (p.Ala94Pro)	GPIHBP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3242178	NM_178172.6(GPIHBP1):c.472C>T (p.Arg158Trp)	GPIHBP1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
GPIHBP1	Strong	Autosomal recessive	hyperlipoproteinemia, type 1D	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GPIHBP1	Orphanet:535458	Familial GPIHBP1 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
GPIHBP1	HGNC:24945	ENSG00000277494	Q8IV16	Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GPIHBP1	Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1	Mediates the transport of lipoprotein lipase LPL from the basolateral to the apical surface of endothelial cells in capillaries.

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)
GPIHBP1	Other/Unknown	no		Toxin/TOLIP, Snake_toxin-like_sf, Ly-6/neurotoxin-like_GPI-ap

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
C1 segment of cervical spinal cord	1
apex of heart	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GPIHBP1	193	broad	marker	apex of heart, C1 segment of cervical spinal cord, spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPIHBP1	1,006

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GPIHBP1	Q8IV16	4

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
Chylomicron remodeling	1	1142.0×	0.003	GPIHBP1
Assembly of active LPL and LIPC lipase complexes	1	601.0×	0.003	GPIHBP1
Retinoid metabolism and transport	1	248.3×	0.005	GPIHBP1
Post-translational modification: synthesis of GPI-anchored proteins	1	167.9×	0.006	GPIHBP1

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
positive regulation of chylomicron remodeling	1	16852.0×	4e-04	GPIHBP1
positive regulation of chylomicron remnant clearance	1	16852.0×	4e-04	GPIHBP1
response to heparin	1	5617.3×	7e-04	GPIHBP1
protein import	1	1685.2×	0.001	GPIHBP1
transcytosis	1	1685.2×	0.001	GPIHBP1
positive regulation of fatty acid biosynthetic process	1	1296.3×	0.002	GPIHBP1
triglyceride catabolic process	1	802.5×	0.002	GPIHBP1
protein localization to cell surface	1	495.6×	0.003	GPIHBP1
triglyceride homeostasis	1	481.5×	0.003	GPIHBP1
cholesterol homeostasis	1	156.0×	0.008	GPIHBP1
protein stabilization	1	66.9×	0.015	GPIHBP1
intracellular protein transport	1	64.8×	0.015	GPIHBP1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GPIHBP1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GPIHBP1

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)
GPIHBP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.