hypercholesterolemia, autosomal dominant, type B

Summary

hypercholesterolemia, autosomal dominant, type B (MONDO:0007751) is a disease caused by APOB (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: APOB (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 3,253
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercholesterolemia, autosomal dominant, type B
Mondo ID	MONDO:0007751
OMIM	144010
SNOMED CT	238081000
UMLS	C1704417
MedGen	309962
GARD	0027779
Is cancer (heuristic)	no

Also known as: hypercholesterolemia, autosomal dominant, type B · hypercholesterolemia, familial, 2

Data availability: 3,253 ClinVar variants · 5 GenCC gene-disease records · 3 cell lines.

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 › familial hypercholesterolemia › hypercholesterolemia, autosomal dominant, type B

Related subtypes (4): hypercholesterolemia, familial, 1, hypercholesterolemia, autosomal dominant, 3, hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency, homozygous familial hypercholesterolemia

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

600 retrieved; paginated sample, class counts are floors:

285 likely benign, 135 uncertain significance, 96 conflicting classifications of pathogenicity, 33 pathogenic, 18 benign/likely benign, 15 benign, 9 likely pathogenic, 9 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068824	NM_000384.3(APOB):c.9615del (p.Asp3205fs)	APOB	Pathogenic	criteria provided, single submitter
1070406	NM_000384.3(APOB):c.7699C>T (p.Gln2567Ter)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1070659	NM_000384.3(APOB):c.6403del (p.Val2135fs)	APOB	Pathogenic	criteria provided, single submitter
1071546	NM_000384.3(APOB):c.8594dup (p.Asn2865fs)	APOB	Pathogenic	criteria provided, single submitter
1174484	NM_000384.3(APOB):c.226_237+1del	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299586	NM_000384.3(APOB):c.11397del (p.Lys3799fs)	APOB	Pathogenic	criteria provided, single submitter
1323319	NM_000384.3(APOB):c.3511G>T (p.Glu1171Ter)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323322	NM_000384.3(APOB):c.1315C>T (p.Arg439Ter)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1323325	NM_000384.3(APOB):c.11040T>G (p.Tyr3680Ter)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330634	NM_000384.3(APOB):c.537+1G>T	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1364654	NM_000384.3(APOB):c.8075_8076dup (p.Leu2693fs)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1369494	NM_000384.3(APOB):c.2979T>A (p.Tyr993Ter)	APOB	Pathogenic	criteria provided, single submitter
1386291	NM_000384.3(APOB):c.7489C>T (p.Gln2497Ter)	APOB	Pathogenic	criteria provided, single submitter
1402036	NM_000384.3(APOB):c.331_332del (p.Ala111fs)	APOB	Pathogenic	criteria provided, single submitter
1406951	NM_000384.3(APOB):c.9960del (p.Phe3320fs)	APOB	Pathogenic	criteria provided, single submitter
1416136	NM_000384.3(APOB):c.11532del (p.Asn3845fs)	APOB	Pathogenic	criteria provided, single submitter
1416940	NM_000384.3(APOB):c.1998C>A (p.Tyr666Ter)	APOB	Pathogenic	criteria provided, single submitter
1432825	NM_000384.3(APOB):c.11465del (p.Val3822fs)	APOB	Pathogenic	criteria provided, single submitter
1453164	NM_000384.3(APOB):c.7966_7969del (p.Phe2656fs)	APOB	Pathogenic	criteria provided, single submitter
1454956	NM_000384.3(APOB):c.10327G>T (p.Glu3443Ter)	APOB	Pathogenic	criteria provided, single submitter
1455782	NM_000384.3(APOB):c.8528_8531dup (p.Phe2845fs)	APOB	Pathogenic	criteria provided, single submitter
1456415	NM_000384.3(APOB):c.7704T>G (p.Tyr2568Ter)	APOB	Pathogenic	criteria provided, single submitter
1458005	NM_000384.3(APOB):c.3778G>T (p.Glu1260Ter)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458186	NM_000384.3(APOB):c.1258G>T (p.Glu420Ter)	APOB	Pathogenic	criteria provided, single submitter
1678797	NM_000384.3(APOB):c.9632dup (p.Asn3211fs)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
1685525	NM_000384.3(APOB):c.13392_13393del (p.Lys4465fs)	APOB	Pathogenic	criteria provided, single submitter
1685526	NM_000384.3(APOB):c.9152_9155del (p.Asn3051fs)	APOB	Pathogenic	criteria provided, single submitter
1685528	NC_000002.12:g.21043539_21043552del	APOB	Pathogenic	criteria provided, single submitter
17881	NM_000384.3(APOB):c.5263_5266del (p.Asn1755fs)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts
17883	NM_000384.3(APOB):c.3997C>T (p.Arg1333Ter)	APOB	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
APOB	Definitive	Autosomal dominant	hypercholesterolemia, autosomal dominant, type B	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APOB	Orphanet:391665	Homozygous familial hypercholesterolemia
AMPD1	Orphanet:45	Adenosine monophosphate deaminase deficiency
LDLR	Orphanet:391665	Homozygous familial hypercholesterolemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOB	HGNC:603	ENSG00000084674	P04114	Apolipoprotein B-100	gencc,clinvar
AMPD1	HGNC:468	ENSG00000116748	P23109	AMP deaminase 1	clinvar
LDLR	HGNC:6547	ENSG00000130164	P01130	Low-density lipoprotein receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APOB	Apolipoprotein B-100	Apolipoprotein B is a major protein constituent of chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100).
AMPD1	AMP deaminase 1	AMP deaminase plays a critical role in energy metabolism.
LDLR	Low-density lipoprotein receptor	Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOB	Other/Unknown	no		Vitellogenin_N, Lipid_transpt_open_b-sht, Lipovitellin_superhlx_dom
AMPD1	Enzyme (other)	yes	3.5.4.6	AMPD, A/AMP_deam_AS, Metal_Hydrolase
LDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
jejunal mucosa	1
liver	1
quadriceps femoris	1
triceps brachii	1
vastus lateralis	1
adrenal tissue	1
lower lobe of lung	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOB	116	broad	marker	jejunal mucosa, liver, ileal mucosa
AMPD1	175	tissue_specific	marker	triceps brachii, vastus lateralis, quadriceps femoris
LDLR	281	ubiquitous	marker	adrenal tissue, lower lobe of lung, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOB	5,244
AMPD1	1,830
LDLR	1,426

Intra-cohort edges

A	B	Sources
APOB	LDLR	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LDLR	P01130	36
APOB	P04114	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AMPD1	P23109	86.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Chylomicron clearance	2	1522.7×	2e-05	APOB, LDLR
LDL clearance	2	362.5×	2e-04	APOB, LDLR
Plasma lipoprotein clearance	2	317.2×	2e-04	APOB, LDLR
Metabolism of fat-soluble vitamins	2	253.8×	2e-04	APOB, LDLR
Visual phototransduction	2	173.0×	4e-04	APOB, LDLR
Retinoid metabolism and transport	2	165.5×	4e-04	APOB, LDLR
Plasma lipoprotein assembly, remodeling, and clearance	2	152.3×	4e-04	APOB, LDLR
Metabolism of vitamins and cofactors	2	77.7×	0.001	APOB, LDLR
Cargo recognition for clathrin-mediated endocytosis	2	69.8×	0.001	APOB, LDLR
Sensory Perception	2	63.4×	0.001	APOB, LDLR
Clathrin-mediated endocytosis	2	56.8×	0.002	APOB, LDLR
Metabolism	3	11.6×	0.002	APOB, AMPD1, LDLR
Scavenging by Class H Receptors	1	951.7×	0.004	APOB
VLDL assembly	1	761.3×	0.004	APOB
Scavenging by Class F Receptors	1	634.4×	0.004	APOB
LDL remodeling	1	634.4×	0.004	APOB
VLDL clearance	1	634.4×	0.004	APOB
Membrane Trafficking	2	24.7×	0.005	APOB, LDLR
Nucleotide salvage	1	380.7×	0.005	AMPD1
Chylomicron assembly	1	380.7×	0.005	APOB
Chylomicron remodeling	1	380.7×	0.005	APOB
Vesicle-mediated transport	2	23.2×	0.005	APOB, LDLR
Scavenging by Class B Receptors	1	346.1×	0.006	APOB
Purine salvage	1	292.8×	0.006	AMPD1
Plasma lipoprotein assembly	1	237.9×	0.008	APOB
Platelet sensitization by LDL	1	223.9×	0.008	APOB
Transport of small molecules	2	16.8×	0.008	APOB, LDLR
Scavenging by Class A Receptors	1	200.3×	0.008	APOB
Binding and Uptake of Ligands by Scavenger Receptors	1	181.3×	0.009	APOB
Regulation of TLR by endogenous ligand	1	165.5×	0.009	APOB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipoprotein catabolic process	2	1605.0×	3e-05	APOB, LDLR
low-density lipoprotein particle clearance	2	660.9×	9e-05	APOB, LDLR
cholesterol transport	2	488.5×	1e-04	APOB, LDLR
artery morphogenesis	2	449.4×	1e-04	APOB, LDLR
cholesterol metabolic process	2	130.6×	9e-04	APOB, LDLR
cholesterol homeostasis	2	104.0×	0.001	APOB, LDLR
regulation of phosphatidylcholine catabolic process	1	2808.7×	0.003	LDLR
receptor-mediated endocytosis involved in cholesterol transport	1	2808.7×	0.003	LDLR
IMP biosynthetic process	1	1872.4×	0.003	AMPD1
negative regulation of astrocyte activation	1	1872.4×	0.003	LDLR
triglyceride mobilization	1	1404.3×	0.003	APOB
plasma lipoprotein particle clearance	1	1404.3×	0.003	LDLR
negative regulation of receptor recycling	1	1123.5×	0.003	LDLR
IMP salvage	1	1123.5×	0.003	AMPD1
cellular response to lipoprotein particle stimulus	1	1123.5×	0.003	APOB
positive regulation of lysosomal protein catabolic process	1	1123.5×	0.003	LDLR
GMP salvage	1	936.2×	0.003	AMPD1
lipoprotein biosynthetic process	1	936.2×	0.003	APOB
cholesterol import	1	936.2×	0.003	LDLR
positive regulation of cholesterol storage	1	802.5×	0.003	APOB
high-density lipoprotein particle clearance	1	802.5×	0.003	LDLR
regulation of protein metabolic process	1	702.2×	0.003	LDLR
negative regulation of protein metabolic process	1	702.2×	0.003	LDLR
amyloid-beta clearance by cellular catabolic process	1	702.2×	0.003	LDLR
negative regulation of microglial cell activation	1	702.2×	0.003	LDLR
AMP metabolic process	1	624.1×	0.004	AMPD1
negative regulation of low-density lipoprotein particle clearance	1	510.7×	0.004	LDLR
regulation of cholesterol biosynthetic process	1	510.7×	0.004	APOB
response to caloric restriction	1	510.7×	0.004	LDLR
positive regulation of gene expression	2	25.8×	0.004	APOB, LDLR

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 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
LDLR	NILOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LDLR	1	4
APOB	0	0
AMPD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NILOTINIB	4	LDLR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LDLR	55	Binding:54, Functional:1
AMPD1	3	Binding:3
APOB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AMPD1	3.5.4.6	AMP deaminase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
NILOTINIB	4	LDLR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LDLR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	AMPD1
E	Difficult family or no structure, no drug	1	APOB

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)
APOB	1	—
AMPD1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04656028	Not specified	ACTIVE_NOT_RECRUITING	Genetic Testing and Motivational Counseling for FH