GeneBe

LPL

protein-coding

lipoprotein lipase, the group of Lipases

Gene summary

LPL encodes lipoprotein lipase, which is expressed in heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism. [provided by RefSeq, Jul 2008]

Previous symbols:
  • LIPD

MANE transcript

NM_000237.3

Inheritance

AD, AR, SD

ClinVar variants

P:178U:217B:263

Top phenotype

Hyperlipidemia, familial combined, 3; Lipoprotein lipase deficiency

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr8:19,901,717-19,967,259

External References & Databases

Ensembl (ENSG00000175445)NCBI Gene (4023)OMIM (609708)HGNC:6677GenCCUniProt (P06858)AlphaFoldClinVar (LPL)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~65.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperlipidemia, familial combined, LPL relatedSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007759

Submitter: Genomics England PanelApp

familial lipoprotein lipase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009387

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

familial lipoprotein lipase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009387

Submitter: Genomics England PanelApp

hyperlipidemia, familial combined, LPL relatedSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0007759

Submitter: PanelApp Australia

familial lipoprotein lipase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009387

Submitter: Natera

hyperlipidemia, familial combined, LPL relatedLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007759

Submitter: Natera

familial lipoprotein lipase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009387

Submitter: Labcorp Genetics (formerly Invitae)

familial lipoprotein lipase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009387

Submitter: G2P

familial lipoprotein lipase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009387

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hyperlipidemia, familial combined, 3; Lipoprotein lipase deficiencyAD/AR

Manifestation: Cardiovascular; Gastrointestinal; Hematologic

Intervention: Cardiovascular; Gastrointestinal; Pharmacogenomic

Rationale: Patients with Hyperlipidemia, familial combinedL are at increased risk of cardiovascular disease, as well as other comorbid conditions, and awareness may allow early medical and lifestyle management to prevent sequelae; In LPL deficiency, treatment centers on medical (eg, inhibitors of APOC3 mRNA have been reported as beneficial related to lower triglyceride measurements) and nutrition therapy (eg, reducing fat intake, alcohol abstinence, as well as antioxidant therapy related to risks of sequelae) aimed to maintain plasma triglyceride concentration less than 1000 mg/dL; In LPL deficiency, gene therapy (Alipogene tiparvovec) is clinically available; Treatment of acute pancreatitis involves fasting with low-calorie infusion; Medical treatment (eg, with fibrates) may be beneficial in adults with LPL deficiency; Certain medications that can affect triglyceride levels should be avoided, and sequelae such as pancreatitis may be precipitated by OCPs

Comments: Heterozygous variants can contribute to Familial combined hyperlipidemia (LPL deficiency is an autosomal recessive disorder)

Refs: 13483896; 13712364; 3630977; 4719678; 6638056; 6645961; 2648155; 2536938; 2110364; 2294743; 1969408; 2121025; 1975597; 2394828; 2010533; 1702428; 1907278; 1752947; 1674945; 2038366; 1530621; 1562620; 1400331; 1598907; 1511985; 1639392; 1512512; 1731801; 1737848; 8096693; 8486765; 8325986; 7906986; 8541837; 7753827; 8755931; 8778602; 9401010; 9738727; 10517255; 10199753; 11134145; 11334614; 15928243; 16174715; 15840743; 16552344; 17032721; 19295657; 20301485; 21159338; 22129523; 22239554; 22438229; 22717743; 23527320; 24142281; 25470695; 30307446Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LPL variants in ClinVar

14 Conditions Cataloged
not providedTotal: 536
Cardiovascular phenotypeTotal: 285
Hyperlipoproteinemia, type ITotal: 205
not specifiedTotal: 78
Hyperlipidemia, familial combined, LPL relatedTotal: 63
LPL-related disorderTotal: 23
Hyperlipidemia, familial combined, susceptibility toTotal: 2
Coronary heart diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000237.3. 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
6
clinvar
244
clinvar
 250
missense
21
clinvar
62
clinvar
211
clinvar
18
clinvar
 312
nonsense
20
clinvar
13
clinvar
1
clinvar
 34
start loss
1
clinvar
1
clinvar
 2
frameshift
31
clinvar
11
clinvar
 42
splice donor/acceptor (+/-2bp)
7
clinvar
11
clinvar
 18
Total80982172621658

Highest pathogenic variant AF is 0.0003556113

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000237.3RefSeqNP_000228.110MANE Select
ENST00000650287.1EnsemblENSP00000497642.110MANE Select
ENST00000519773.1EnsemblENSP00000431028.12Standard
ENST00000520959.5EnsemblENSP00000428496.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Glycerolipid metabolism - Homo sapiens (human)
  • Alzheimer,s disease - Homo sapiens (human)
  • Cholesterol metabolism - Homo sapiens (human)
  • PPAR signaling pathway - Homo sapiens (human)
  • Statin Pathway, Pharmacodynamics

Biological Process

  • fatty acid biosynthetic process
  • triglyceride metabolic process
  • phospholipid metabolic process
  • response to cold
  • response to bacterium

Molecular Function

  • lipoprotein lipase activity
  • phospholipase activity
  • triglyceride lipase activity
  • signaling receptor binding
  • protein binding

Cellular Component

  • extracellular region
  • extracellular space
  • plasma membrane
  • cell surface
  • anchored component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000311322
Coding exons
9
Length
65542
Individuals with no LoFs
103778
Homozygous LoFs
1212
Heterozygous LoFs
20758
Defined
125748
p
0.0915
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.5032832601.090.00001433129
Missense (PolyPhen)93103.560.8981253
Synonymous-2.081271011.260.00000608897
Loss of Function1.211723.30.7300.00000108289

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0720.071notable
Latino/Admixed American0.0550.055notable
Ashkenazi Jewish0.100.10notable
East Asian0.110.11notable
Finnish0.0880.088notable
European (Non-Finnish)0.100.10notable
South Asian0.0960.096notable
Other0.0950.095notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: The primary function of this lipase is the hydrolysis of triglycerides of circulating chylomicrons and very low density lipoproteins (VLDL) (PubMed:27578112). Binding to heparin sulfate proteogylcans at the cell surface is vital to the function. The apolipoprotein, APOC2, acts as a coactivator of LPL activity in the presence of lipids on the luminal surface of vascular endothelium (By similarity). {ECO:0000250, ECO:0000269|PubMed:11342582, ECO:0000269|PubMed:27578112}.;
Disease
DISEASE: Lipoprotein lipase deficiency (LPL deficiency) [MIM:238600]: Recessive disorder usually manifesting in childhood. On a normal diet, patients often present with abdominal pain, hepatosplenomegaly, lipemia retinalis, eruptive xanthomata, and massive hypertriglyceridemia, sometimes complicated with acute pancreatitis. {ECO:0000269|PubMed:10660334, ECO:0000269|PubMed:10787434, ECO:0000269|PubMed:11068186, ECO:0000269|PubMed:11099402, ECO:0000269|PubMed:11134145, ECO:0000269|PubMed:11441134, ECO:0000269|PubMed:12204001, ECO:0000269|PubMed:12641539, ECO:0000269|PubMed:12966036, ECO:0000269|PubMed:1400331, ECO:0000269|PubMed:1479292, ECO:0000269|PubMed:14984478, ECO:0000269|PubMed:15185149, ECO:0000269|PubMed:1521525, ECO:0000269|PubMed:15256764, ECO:0000269|PubMed:15877202, ECO:0000269|PubMed:1598907, ECO:0000269|PubMed:1619366, ECO:0000269|PubMed:1639392, ECO:0000269|PubMed:1674945, ECO:0000269|PubMed:1702428, ECO:0000269|PubMed:1730727, ECO:0000269|PubMed:1752947, ECO:0000269|PubMed:1907278, ECO:0000269|PubMed:1969408, ECO:0000269|PubMed:1975597, ECO:0000269|PubMed:2010533, ECO:0000269|PubMed:2038366, ECO:0000269|PubMed:2110364, ECO:0000269|PubMed:2121025, ECO:0000269|PubMed:27578112, ECO:0000269|PubMed:7647785, ECO:0000269|PubMed:7806969, ECO:0000269|PubMed:7906986, ECO:0000269|PubMed:7912254, ECO:0000269|PubMed:7999071, ECO:0000269|PubMed:8077845, ECO:0000269|PubMed:8096693, ECO:0000269|PubMed:8135797, ECO:0000269|PubMed:8288243, ECO:0000269|PubMed:8301230, ECO:0000269|PubMed:8325986, ECO:0000269|PubMed:8486765, ECO:0000269|PubMed:8728326, ECO:0000269|PubMed:8778602, ECO:0000269|PubMed:8858123, ECO:0000269|PubMed:8872057, ECO:0000269|PubMed:8956048, ECO:0000269|PubMed:8956052, ECO:0000269|PubMed:9279761, ECO:0000269|PubMed:9298816, ECO:0000269|PubMed:9498099, ECO:0000269|PubMed:9662394, ECO:0000269|PubMed:9714430, ECO:0000269|PubMed:9719626}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.197
RVIS EVS
0.53
RVIS percentile EVS
80.96

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.990

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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