GeneBe

APOC3

protein-coding

apolipoprotein C3, the group of Apolipoproteins

Gene summary

This gene encodes a protein component of triglyceride (TG)-rich lipoproteins (TRLs) including very low density lipoproteins (VLDL), high density lipoproteins (HDL) and chylomicrons. The encoded protein plays a role in role in the metabolism of these TRLs through multiple modes. This protein has been shown to promote the secretion of VLDL1, inhibit lipoprotein lipase enzyme activity, and delay catabolism of TRL remnants. Mutations in this gene are associated with low plasma triglyceride levels and reduced risk of ischemic cardiovascular disease, and hyperalphalipoproteinemia, which is characterized by elevated levels of high density lipoprotein (HDL) and HDL cholesterol in human patients. This gene and other related genes comprise an apolipoprotein gene cluster on chromosome 11. [provided by RefSeq, Sep 2017]

MANE transcript

NM_000040.3

Inheritance

AD

ClinVar variants

P:3U:36B:22

Top phenotype

Apolipoprotein C-III deficiency

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr11:116,829,706-116,833,072

External References & Databases

Ensembl (ENSG00000110245)NCBI Gene (345)OMIM (107720)HGNC:610GenCCUniProt (P02656)AlphaFoldClinVar (APOC3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~3.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

apolipoprotein c-III deficiencyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013534

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Apolipoprotein C-III deficiencyAD

Manifestation: Cardiovascular

Intervention: General

Rationale: The clinical applicability of Hyperalophalipoproteinemia 2 is unclear, though variants may be related to lower triglyceride levels and protection against cardiovascular disease

Refs: 2914370; 2022742; 16813599; 19074352; 24941081; 24941082; 25225788Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to APOC3 variants in ClinVar

10 Conditions Cataloged
Cardiovascular phenotypeTotal: 45
not providedTotal: 37
not specifiedTotal: 12
Apolipoprotein c-III deficiencyTotal: 8
Coronary heart diseaseTotal: 4
APOC3-related disorderTotal: 1
High density lipoprotein deficiency, Detroit typeTotal: 1
Apolipoprotein C-III, nonglycosylatedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000040.3. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
18
clinvar
 20
missense
2
clinvar
31
clinvar
3
clinvar
 36
nonsense
1
clinvar
 1
start loss
1
clinvar
 1
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
1
clinvar
1
clinvar
 2
Total303622061

Highest pathogenic variant AF is 0.000026643535

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000040.3RefSeqNP_000031.13MANE Select
ENST00000227667.8EnsemblENSP00000227667.23MANE Select
ENST00000375345.3EnsemblENSP00000364494.13Standard
ENST00000375345.4EnsemblENSP00000364494.13Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cholesterol metabolism - Homo sapiens (human)
  • PPAR signaling pathway - Homo sapiens (human)
  • Statin Pathway, Pharmacodynamics
  • PPAR Alpha Pathway
  • Nuclear Receptors Meta-Pathway

Biological Process

  • retinoid metabolic process
  • triglyceride metabolic process
  • G protein-coupled receptor signaling pathway
  • negative regulation of triglyceride catabolic process
  • negative regulation of very-low-density lipoprotein particle remodeling

Molecular Function

  • phospholipid binding
  • cholesterol binding
  • enzyme regulator activity
  • lipase inhibitor activity
  • high-density lipoprotein particle receptor binding

Cellular Component

  • extracellular region
  • extracellular space
  • early endosome
  • very-low-density lipoprotein particle
  • intermediate-density lipoprotein particle

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000227667
Coding exons
3
Length
3367
Individuals with no LoFs
125050
Homozygous LoFs
2
Heterozygous LoFs
528
Defined
125580
p
0.00211
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.05765957.81.020.00000336634
Missense (PolyPhen)1315.1330.85903196
Synonymous0.3102426.00.9230.00000186197
Loss of Function0.35633.740.8012.45e-734

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00150.0015notable
Latino/Admixed American0.00190.0019notable
Ashkenazi Jewish0.00200.0020notable
East Asian0.000110.00011rare
Finnish0.000830.00083rare
European (Non-Finnish)0.00280.0028notable
South Asian0.00200.0019notable
Other0.00330.0033notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Component of triglyceride-rich very low density lipoproteins (VLDL) and high density lipoproteins (HDL) in plasma (PubMed:18201179, PubMed:22510806). Plays a multifaceted role in triglyceride homeostasis (PubMed:18201179, PubMed:22510806). Intracellularly, promotes hepatic very low density lipoprotein 1 (VLDL1) assembly and secretion; extracellularly, attenuates hydrolysis and clearance of triglyceride-rich lipoproteins (TRLs) (PubMed:18201179, PubMed:22510806). Impairs the lipolysis of TRLs by inhibiting lipoprotein lipase and the hepatic uptake of TRLs by remnant receptors (PubMed:18201179, PubMed:22510806). Formed of several curved helices connected via semiflexible hinges, so that it can wrap tightly around the curved micelle surface and easily adapt to the different diameters of its natural binding partners (PubMed:18408013). {ECO:0000269|PubMed:18408013, ECO:0000303|PubMed:18201179, ECO:0000303|PubMed:22510806}.;
Disease
DISEASE: Hyperalphalipoproteinemia 2 (HALP2) [MIM:614028]: A condition characterized by high levels of high density lipoprotein (HDL) and increased HDL cholesterol levels. {ECO:0000269|PubMed:2022742}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.731

Intolerance Scores

LoFtool
0.606
RVIS EVS
0.37
RVIS percentile EVS
74.95

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.967

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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