ANGPTL3
protein-codingangiopoietin like 3, the group of Angiopoietin like family|Receptor ligands|Fibrinogen C domain containing
Gene summary
This gene encodes a member of a family of secreted proteins that function in angiogenesis. The encoded protein, which is expressed predominantly in the liver, is further processed into an N-terminal coiled-coil domain-containing chain and a C-terminal fibrinogen chain. The N-terminal chain is important for lipid metabolism, while the C-terminal chain may be involved in angiogenesis. Mutations in this gene cause familial hypobetalipoproteinemia type 2. [provided by RefSeq, Aug 2015]
- ANGPT5
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~8.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011505
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011505
Submitter: ClinGen
The relationship between *ANGPTL3* and familial hypobetalipoproteinemia 2 inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of July, 2022. This association was made using case-level and experimental data. Familial hypobetalipoproteinemia 2 is characterized by a combined deficiency of plasma lipids: very low VLDL, LDL, and HDL levels, and consequently low total TG and cholesterol levels (PMID: 26754661). The *ANGPTL3* gene encodes a member of a family of secreted proteins that function in lipid metabolism and angiogenesis. Summary of Case Level Data (12 points): The association is seen in at least 7 probands with mostly predicted or established loss-of-function variants in 5 publications (PMID: 22155345, 22659251, 20942659, 22247256, 22062970). Variants in this gene segregated with disease in 34 additional family members (PMID: 20942659). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is biallelic loss of function. Some heterozygous carriers are occasionally noted to have plasma lipid levels in the disease range; however, most carriers have plasma lipid levels in the normal range. Only individuals with biallelic variants were scored for this curation. Summary of Experimental Data (6 points): The ANGPTL3 protein is almost exclusively expressed in the liver (PMID: 11788823). Mouse and zebrafish models with *ANGPTL3* alterations recapitulate the human hypobetalipoproteinemia phenotype (PMID: 11788823, 24685482). Introduction of WT gene into the *Angptl3*-/- mouse model restores lipid levels (PMID: 11788823). In-vitro functional assays elucidate the role of *ANGPTL3* mutations in disease, which acts through reversible inhibition of LPL (PMID: 12097324, 26754661, 19028676). *ANGPTL3* is a therapeutic target to lower lipid levels in dyslipidemia, and studies have been conducted in mice, monkeys and humans (PMID: 25964512, 28538111). In summary, the *ANGPTL3*-Familial Hypobetalipoproteinemia 2 gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0011505
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011505
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Gastrointestinal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Unlike hypobetalipoproteinemia due to variants in APOB, individuals with variants in ANGPTL3 do not appear to to have increased susceptibility to hepatic steatosis or gastrointestinal or cardiovascular manifestations compared to unaffected relatives; Heterozygous individuals may demonstrate laboratory-based manifestations (eg, lower plasma LDL and triglycerides)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ANGPTL3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_014495.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 37 | 2 | 39 | |||
| missense | 1 | 64 | 7 | 1 | 73 | |
| nonsense | 4 | 1 | 5 | |||
| start loss | 0 | |||||
| frameshift | 3 | 5 | 8 | |||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 2 | 1 | 6 | |
| Total | 9 | 7 | 67 | 45 | 3 | 131 |
Highest pathogenic variant AF is 0.00043469804
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_055310.1 | 7 | MANE Select | |
| Ensembl | ENSP00000360170.3 | 7 | MANE Select | |
| Ensembl | ENSP00000565544.1 | 6 | Standard | |
| Ensembl | ENSP00000565545.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| angptl3 | Danio rerio | Structure: intestine Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cholesterol metabolism - Homo sapiens (human)
- Transport of small molecules
- Assembly of active LPL and LIPC lipase complexes
- Plasma lipoprotein assembly, remodeling, and clearance
- Plasma lipoprotein remodeling
Biological Process
- angiogenesis
- glycerol metabolic process
- fatty acid metabolic process
- phospholipid metabolic process
- cell-matrix adhesion
Molecular Function
- enzyme inhibitor activity
- phospholipase inhibitor activity
- integrin binding
- growth factor activity
- heparin binding
Cellular Component
- extracellular region
- extracellular space
- early endosome
- Golgi apparatus
- cell surface
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371129
- Coding exons
- 7
- Length
- 8673
- Individuals with no LoFs
- 125547
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 179
- Defined
- 125726
- p
- 0.000712
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0942 | 232 | 228 | 1.02 | 0.0000106 | 3042 |
| Missense (PolyPhen) | 68 | 58.835 | 1.1558 | 809 | ||
| Synonymous | -0.631 | 91 | 83.7 | 1.09 | 0.00000437 | 809 |
| Loss of Function | 0.432 | 21 | 23.2 | 0.903 | 0.00000115 | 293 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0022 | 0.0022 | notable |
| Latino/Admixed American | 0.00078 | 0.00055 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00045 | 0.00044 | rare |
| Finnish | 0.00010 | 0.000092 | rare |
| European (Non-Finnish) | 0.00084 | 0.00076 | rare |
| South Asian | 0.00078 | 0.00069 | rare |
| Other | 0.0012 | 0.0011 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism (PubMed:11788823, PubMed:12909640, PubMed:23661675, PubMed:25495645). Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity). Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324, PubMed:19318355, PubMed:20581395). Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids (PubMed:17110602, PubMed:19028676). Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (PubMed:12565906). Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity). Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity). {ECO:0000250|UniProtKB:Q9R182, ECO:0000269|PubMed:11788823, ECO:0000269|PubMed:12097324, ECO:0000269|PubMed:12565906, ECO:0000269|PubMed:12909640, ECO:0000269|PubMed:17110602, ECO:0000269|PubMed:19028676, ECO:0000269|PubMed:19318355, ECO:0000269|PubMed:20581395, ECO:0000269|PubMed:23661675, ECO:0000269|PubMed:25495645, ECO:0000305|PubMed:20581395}.; FUNCTION: Involved in angiogenesis. Binds to endothelial cells via integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt signaling pathways and induces cell adhesion and cell migration (PubMed:11877390). Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling (PubMed:18535744). May increase the motility of podocytes. May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS (By similarity). {ECO:0000250|UniProtKB:Q9R182, ECO:0000269|PubMed:11877390, ECO:0000269|PubMed:18535744}.;
- Disease
- DISEASE: Hypobetalipoproteinemia, familial, 2 (FHBL2) [MIM:605019]: A disorder of lipid metabolism characterized by less than 5th percentile age- and sex-specific levels of low density lipoproteins, and dietary fat malabsorption. Affected individuals present with combined hypolipidemia, consisting of extremely low plasma levels of LDL cholesterol, HDL cholesterol, and triglycerides. {ECO:0000269|PubMed:20942659}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=May be involved in atherosclerosis. Plasma levels are closely associated with arterial wall thickness. {ECO:0000305|PubMed:17191020}.; DISEASE: Note=May be involved in nephrotic syndrome. {ECO:0000305|PubMed:25710887}.;
Intolerance Scores
- LoFtool
- 0.869
- RVIS EVS
- -0.11
- RVIS percentile EVS
- 45.26
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0141
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |