APOB

apolipoprotein B, the group of Apolipoproteins

Basic information

Region (hg38): 2:21001428-21044073

Links

ENSG00000084674 ∙ NCBI:338 ∙ OMIM:107730 ∙ HGNC:603 ∙ Uniprot:P04114 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypercholesterolemia, autosomal dominant, type B (Strong), mode of inheritance: AD
• familial hypobetalipoproteinemia 1 (Strong), mode of inheritance: AR
• familial hypobetalipoproteinemia 1 (Strong), mode of inheritance: AR
• hypercholesterolemia, autosomal dominant, type B (Definitive), mode of inheritance: AD
• homozygous familial hypercholesterolemia (Supportive), mode of inheritance: AR
• familial hypobetalipoproteinemia 1 (Strong), mode of inheritance: AR
• hypercholesterolemia, autosomal dominant, type B (Strong), mode of inheritance: AD
• familial hypobetalipoproteinemia 1 (Strong), mode of inheritance: AD
• hypercholesterolemia, autosomal dominant, type B (Definitive), mode of inheritance: AD
• familial hypobetalipoproteinemia 1 (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypercholesterolemia, familial, 2; Hypobetalipoproteinemia, familial 1	AD/AR	Cardiovascular; Gastrointestinal	Some variants may be associated with familial hypercholesterolemia, and dietary/lifestyle/medical measures (eg, with statins) may be beneficial to reduce the risk of sequelae including coronary artery disease, with evidence that early diagnosis and management improves outcomes; In hypobetalipoproteinemia, dietary measures (eg, with a low fat diet and supplementation of essential fatty acids and fat-soluble vitamins) can be beneficial, and early initiation can prevent/decrease severe sequelae; In Hypercholesterolemia, familial, 2, medical management (with inclisiran, a small interfering RNA), has shown evidence of benefit related to parameters such as LDL levels	Cardiovascular; Gastrointestinal; Hematologic; Neurologic; Ophthalmologic	221546; 7229035; 3771801; 3680528; 3473077; 3584472; 2843815; 2903181; 3399894; 2567736; 2574033; 2563166; 3477815; 2614276; 2725600; 2280177; 2164382; 2310429; 2312735; 1939657; 2022744; 1360085; 1562615; 1600334; 1424233; 1466657; 8215738; 8318993; 8318509; 7711417; 8305410; 8004802; 7883971; 8723684; 8792774; 9108789; 9081691; 9603795; 10952765; 11781700; 11494965; 11940084; 12124991;15984016; 17158591; 18492086; 18354102; 20686565; 21981844; 24288038; 31618540; 32187462; 32197277
Variants in multiple related genes (eg, LDLR) may have additive effects

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the APOB gene.

• Cardiovascular phenotype (1465 variants)
• Hypercholesterolemia, autosomal dominant, type B;Familial hypobetalipoproteinemia 1 (890 variants)
• Familial hypobetalipoproteinemia 1;Hypercholesterolemia, autosomal dominant, type B (880 variants)
• not provided (531 variants)
• Hypercholesterolemia, autosomal dominant, type B (332 variants)
• Familial hypobetalipoproteinemia 1 (305 variants)
• Hypercholesterolemia, familial, 1 (275 variants)
• not specified (177 variants)
• Inborn genetic diseases (107 variants)
• Familial hypercholesterolemia (86 variants)
• Familial hypobetalipoproteinemia (36 variants)
• APOB-related condition (24 variants)
• Hypobetalipoproteinemia (6 variants)
• APOB-Related Disorders (5 variants)
• Warfarin response (5 variants)
• Homozygous familial hypercholesterolemia (3 variants)
• Hypercholesterolemia (3 variants)
• Early-onset coronary artery disease (2 variants)
• Stroke disorder (2 variants)
• Primary familial dilated cardiomyopathy (1 variants)
• Hypercholesterolemia, autosomal dominant, type B;Muscle AMP deaminase deficiency (1 variants)
• Spastic ataxia (1 variants)
• Marfanoid habitus and intellectual disability (1 variants)
• APOB-related disorder (1 variants)
• APOB POLYMORPHISM IN SIGNAL PEPTIDE (1 variants)
• Transient hyperlipidemia (1 variants)
• Hypercholesterolemia, autosomal dominant, 3 (1 variants)
• Triangular shaped proximal phalanx of the thumb;Neutrophilia in presence of infection;Isolated systolic hypertension (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the APOB gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			22	830	9	861
missense	3	5	1181	120	10	1319
nonsense	29	11	10			50
start loss						0
frameshift	49	15	10		1	75
inframe indel			16	2	1	19
splice donor/acceptor (+/-2bp)	4	12	1			17
splice region			18	36	2	56
non coding			18	38	12	68
Total	85	43	1258	990	33

Highest pathogenic variant AF is 0.0000197

Variants in APOB

This is a list of pathogenic ClinVar variants found in the APOB region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-21001465-C-T		Hypercholesterolemia, autosomal dominant, type B • Familial hypobetalipoproteinemia 1	Uncertain significance (Jan 13, 2018)
2-21001501-T-C		Hypercholesterolemia, autosomal dominant, type B • Familial hypobetalipoproteinemia 1 • Familial hypobetalipoproteinemia 1;Hypercholesterolemia, autosomal dominant, type B	Conflicting classifications of pathogenicity (Jul 17, 2023)
2-21001523-G-T		Hypercholesterolemia, familial, 1 • Familial hypobetalipoproteinemia	Uncertain significance (Jun 14, 2016)
2-21001550-C-A		Familial hypobetalipoproteinemia 1 • Hypercholesterolemia, autosomal dominant, type B	Conflicting classifications of pathogenicity (Jan 13, 2018)
2-21001551-G-A		Hypercholesterolemia, autosomal dominant, type B • Familial hypobetalipoproteinemia 1	Conflicting classifications of pathogenicity (Apr 01, 2023)
2-21001559-G-A		Hypercholesterolemia, familial, 1	Uncertain significance (Jun 14, 2016)
2-21001600-T-A		Familial hypobetalipoproteinemia 1 • Hypercholesterolemia, autosomal dominant, type B	Uncertain significance (Jan 12, 2018)
2-21001613-C-T		Hypercholesterolemia, autosomal dominant, type B • Familial hypobetalipoproteinemia 1	Uncertain significance (Jan 12, 2018)
2-21001645-A-G		Hypercholesterolemia, autosomal dominant, type B • Familial hypobetalipoproteinemia 1	Uncertain significance (Jan 13, 2018)
2-21001699-A-G		Hypercholesterolemia, autosomal dominant, type B • Familial hypobetalipoproteinemia 1	Conflicting classifications of pathogenicity (Apr 27, 2017)
2-21001719-C-A		Familial hypobetalipoproteinemia 1 • Hypercholesterolemia, autosomal dominant, type B • Familial hypercholesterolemia • Familial hypobetalipoproteinemia 1;Hypercholesterolemia, autosomal dominant, type B	Conflicting classifications of pathogenicity (Dec 07, 2022)
2-21001739-G-A		Familial hypobetalipoproteinemia 1;Hypercholesterolemia, autosomal dominant, type B	Likely benign (Dec 24, 2021)
2-21001742-A-G		Hypercholesterolemia, familial, 1 • Familial hypercholesterolemia • Hypercholesterolemia, autosomal dominant, type B • Familial hypobetalipoproteinemia 1 • not specified • Hypercholesterolemia, autosomal dominant, type B;Familial hypobetalipoproteinemia 1 • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Jan 31, 2024)
2-21001743-G-T		Familial hypobetalipoproteinemia 1;Hypercholesterolemia, autosomal dominant, type B	Likely benign (Dec 22, 2022)
2-21001744-T-C		Familial hypercholesterolemia	Uncertain significance (Feb 26, 2019)
2-21001747-G-A		Cardiovascular phenotype	Likely benign (Dec 28, 2023)
2-21001750-C-T		Familial hypercholesterolemia • Familial hypobetalipoproteinemia 1;Hypercholesterolemia, autosomal dominant, type B	Uncertain significance (Oct 20, 2021)
2-21001752-C-G		Familial hypercholesterolemia • Hypercholesterolemia, autosomal dominant, type B;Familial hypobetalipoproteinemia 1 • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Nov 28, 2023)
2-21001757-A-G		Familial hypobetalipoproteinemia 1;Hypercholesterolemia, autosomal dominant, type B	Likely benign (May 11, 2022)
2-21001759-C-A		Cardiovascular phenotype	Uncertain significance (Feb 12, 2023)
2-21001763-C-A		Hypercholesterolemia, autosomal dominant, type B • Familial hypobetalipoproteinemia 1	Uncertain significance (Jan 13, 2018)
2-21001768-T-C		Hypercholesterolemia, familial, 1 • Hypercholesterolemia, autosomal dominant, type B;Familial hypobetalipoproteinemia 1 • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Aug 17, 2023)
2-21001769-G-T		Familial hypobetalipoproteinemia 1;Hypercholesterolemia, autosomal dominant, type B	Uncertain significance (Jun 13, 2021)
2-21001771-A-G		Familial hypercholesterolemia • Cardiovascular phenotype • Hypercholesterolemia, autosomal dominant, type B;Familial hypobetalipoproteinemia 1	Conflicting classifications of pathogenicity (Dec 18, 2023)
2-21001774-G-T		Familial hypercholesterolemia	Uncertain significance (Nov 11, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
APOB	protein_coding	protein_coding	ENST00000233242	29	42645

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.92e-16	1.00	125554	0	194	125748	0.000772

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.70	2482	2.25e+3	1.10	0.000119	30090
Missense in Polyphen		644	609.82	1.0561		8417
Synonymous	-1.40	953	900	1.06	0.0000498	8901
Loss of Function	7.20	56	152	0.369	0.00000783	2096

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00128	0.00127
Ashkenazi Jewish	0.000696	0.000695
East Asian	0.000492	0.000489
Finnish	0.000278	0.000277
European (Non-Finnish)	0.000885	0.000879
Middle Eastern	0.000492	0.000489
South Asian	0.00133	0.00127
Other	0.000981	0.000978

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Apolipoprotein B is a major protein constituent of chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100). Apo B-100 functions as a recognition signal for the cellular binding and internalization of LDL particles by the apoB/E receptor.
• Disease: DISEASE: Hypobetalipoproteinemia, familial, 1 (FHBL1) [MIM:615558]: A disorder of lipid metabolism characterized by less than 5th percentile age- and sex-specific levels of low density lipoproteins, and dietary fat malabsorption. Clinical presentation may vary from no symptoms to severe gastrointestinal and neurological dysfunction similar to abetalipoproteinemia. {ECO:0000269|PubMed:12551903, ECO:0000269|PubMed:21981844, ECO:0000269|PubMed:27206948}. Note=The disease is caused by mutations affecting the gene represented in this entry. Most cases of FHBL1 result from nonsense mutations in the APOB gene that lead to a premature stop codon, which generate prematurely truncated apo B protein products (PubMed:21981844). {ECO:0000269|PubMed:21981844}.; DISEASE: Familial ligand-defective apolipoprotein B-100 (FDB) [MIM:144010]: Dominantly inherited disorder of lipoprotein metabolism leading to hypercholesterolemia and increased proneness to coronary artery disease (CAD). The plasma cholesterol levels are dramatically elevated due to impaired clearance of LDL particles by defective APOB/E receptors. {ECO:0000269|PubMed:21382890, ECO:0000269|PubMed:2563166, ECO:0000269|PubMed:7883971, ECO:0000269|PubMed:9259199}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in APOB associated with defects in other genes (polygenic) can contribute to hypocholesterolemia.
• Pathway: Fat digestion and absorption - Homo sapiens (human);Vitamin digestion and absorption - Homo sapiens (human);Cholesterol metabolism - Homo sapiens (human);Statin Pathway, Pharmacodynamics;Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate Metabolism;Statin Pathway;Signaling by GPCR;Signal Transduction;Metabolism of fat-soluble vitamins;Chylomicron assembly;Vesicle-mediated transport;VLDL assembly;Plasma lipoprotein assembly;Membrane Trafficking;Chylomicron remodeling;LDL remodeling;Post-translational protein phosphorylation;Toll-Like Receptors Cascades;Post-translational protein modification;Metabolism of proteins;Chylomicron clearance;Innate Immune System;Immune System;Metabolism;LDL clearance;VLDL clearance;Plasma lipoprotein clearance;Transport of small molecules;Metabolism of vitamins and cofactors;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Clathrin-mediated endocytosis;Cell surface interactions at the vascular wall;Hemostasis;FOXA1 transcription factor network;Plasma lipoprotein assembly, remodeling, and clearance;Retinoid metabolism and transport;Cargo recognition for clathrin-mediated endocytosis;Regulation of TLR by endogenous ligand;G alpha (i) signalling events;Plasma lipoprotein remodeling;Visual phototransduction;Scavenging by Class B Receptors;Scavenging by Class H Receptors;Binding and Uptake of Ligands by Scavenger Receptors;Scavenging by Class A Receptors;Platelet sensitization by LDL;Platelet homeostasis;Scavenging by Class F Receptors;GPCR downstream signalling;amb2 Integrin signaling (Consensus)

Recessive Scores

• pRec: 0.883

Intolerance Scores

• loftool: 0.732
• rvis_EVS: 1.42
• rvis_percentile_EVS: 94.85

Haploinsufficiency Scores

• pHI: 0.450
• hipred: N
• hipred_score: 0.481
• ghis: 0.538

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.983

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Apob
• Phenotype: pigmentation phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); liver/biliary system phenotype; embryo phenotype; immune system phenotype; vision/eye phenotype; muscle phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: apoba
• Affected structure: subintestinal vein
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: retinoid metabolic process;in utero embryonic development;toll-like receptor signaling pathway;triglyceride mobilization;receptor-mediated endocytosis;spermatogenesis;nervous system development;cholesterol metabolic process;fertilization;response to virus;response to carbohydrate;post-embryonic development;response to selenium ion;positive regulation of gene expression;positive regulation of macrophage derived foam cell differentiation;positive regulation of lipid storage;positive regulation of cholesterol storage;triglyceride catabolic process;cholesterol transport;flagellated sperm motility;response to estradiol;response to lipopolysaccharide;cholesterol efflux;chylomicron remodeling;low-density lipoprotein particle remodeling;chylomicron assembly;very-low-density lipoprotein particle assembly;chylomicron remnant clearance;low-density lipoprotein particle clearance;very-low-density lipoprotein particle clearance;lipoprotein biosynthetic process;lipoprotein catabolic process;cholesterol homeostasis;lipoprotein transport;post-translational protein modification;cellular protein metabolic process;regulation of cholesterol biosynthetic process;artery morphogenesis;leukocyte migration;membrane organization;cellular response to tumor necrosis factor;cellular response to prostaglandin stimulus
• Cellular component: extracellular region;extracellular space;cytoplasm;early endosome;endoplasmic reticulum lumen;endoplasmic reticulum membrane;smooth endoplasmic reticulum;cytosol;plasma membrane;endosome membrane;clathrin-coated endocytic vesicle membrane;endosome lumen;mature chylomicron;chylomicron remnant;very-low-density lipoprotein particle;low-density lipoprotein particle;intermediate-density lipoprotein particle;high-density lipoprotein particle;chylomicron;neuronal cell body;lysosomal lumen;intracellular membrane-bounded organelle;extracellular exosome;endoplasmic reticulum exit site;endocytic vesicle lumen
• Molecular function: protein binding;phospholipid binding;heparin binding;cholesterol transporter activity;lipase binding;low-density lipoprotein particle receptor binding