GeneBe

LCAT

protein-coding

lecithin-cholesterol acyltransferase

Gene summary

This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000229.2

Inheritance

AR

ClinVar variants

P:42U:154B:135

Top phenotype

Lecithin:cholesterol acyltransferase deficiency (Norum disease); Fish-eye disease

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr16:67,939,750-67,944,131

External References & Databases

Ensembl (ENSG00000213398)NCBI Gene (3931)OMIM (606967)HGNC:6522GenCCUniProt (P04180)AlphaFoldClinVar (LCAT)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~4.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

fish eye diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007620

Submitter: PanelApp Australia

Norum diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009515

Submitter: Orphanet

fish eye diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007620

Submitter: G2P

LCAT deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018999

Submitter: Ambry Genetics

Norum diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009515

Submitter: PanelApp Australia

fish eye diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007620

Submitter: Labcorp Genetics (formerly Invitae)

fish eye diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007620

Submitter: Orphanet

Clinical Genomic Database (CGD)

Lecithin:cholesterol acyltransferase deficiency (Norum disease); Fish-eye diseaseAR

Manifestation: Biochemical; Cardiovascular; Hematologic; Ophthalmologic; Renal

Intervention: Cardiovascular; Renal

Rationale: Dietary measures (eg, reducing fat intake) may be beneficial in controlling LDL and decreasing sequelae; In LCAT deficiency, medical treatment related to renal disease (eg, with ACE inhibitors) may preserve renal function, though renal transplant may be required

Refs: 5704704; 408950; 7156322; 7148518; 6624548; 6695915; 3661502; 1898657; 2370048; 2052566; 9180249; 9884427; 18042612; 21901787; 22108153; 22189200; 22701329; 23043194; 23391322; 23412821; 23522979Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LCAT variants in ClinVar

8 Conditions Cataloged
Cardiovascular phenotypeTotal: 217
not providedTotal: 136
Norum diseaseTotal: 74
Fish-eye diseaseTotal: 73
LCAT deficiencyTotal: 34
LCAT-related disorderTotal: 10
not specifiedTotal: 4
Decreased circulating HDL-C concentrationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000229.2. 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
4
clinvar
120
clinvar
 124
missense
12
clinvar
13
clinvar
146
clinvar
15
clinvar
 186
nonsense
2
clinvar
5
clinvar
 7
start loss
0
frameshift
1
clinvar
7
clinvar
1
clinvar
 9
splice donor/acceptor (+/-2bp)
2
clinvar
3
clinvar
 5
Total15271541350331

Highest pathogenic variant AF is 0.00006200543

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000229.2RefSeqNP_000220.16MANE Select
ENST00000264005.10EnsemblENSP00000264005.56MANE Select
ENST00000570369.5EnsemblENSP00000459014.13Standard
ENST00000570396.1EnsemblENSP00000459291.12Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Glycerophospholipid metabolism - Homo sapiens (human)
  • Cholesterol metabolism - Homo sapiens (human)
  • Statin Pathway, Pharmacodynamics
  • Composition of Lipid Particles
  • Statin Pathway

Biological Process

  • phospholipid metabolic process
  • phosphatidylcholine biosynthetic process
  • cholesterol metabolic process
  • cholesterol transport
  • very-low-density lipoprotein particle remodeling

Molecular Function

  • phosphatidylcholine-sterol O-acyltransferase activity
  • protein binding
  • apolipoprotein A-I binding

Cellular Component

  • extracellular region
  • extracellular space
  • high-density lipoprotein particle
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000264005
Coding exons
6
Length
4382
Individuals with no LoFs
125730
Homozygous LoFs
0
Heterozygous LoFs
14
Defined
125744
p
0.0000557
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.322032630.7700.00001812845
Missense (PolyPhen)4463.6170.69163694
Synonymous-0.03461131131.000.00000783913
Loss of Function2.71517.10.2927.57e-7184

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000880.000088rare
South Asian0.0000980.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Central enzyme in the extracellular metabolism of plasma lipoproteins. Synthesized mainly in the liver and secreted into plasma where it converts cholesterol and phosphatidylcholines (lecithins) to cholesteryl esters and lysophosphatidylcholines on the surface of high and low density lipoproteins (HDLs and LDLs) (PubMed:10329423, PubMed:19065001, PubMed:26195816). The cholesterol ester is then transported back to the liver. Has a preference for plasma 16:0-18:2 or 18:O-18:2 phosphatidylcholines (PubMed:8820107). Also produced in the brain by primary astrocytes, and esterifies free cholesterol on nascent APOE- containing lipoproteins secreted from glia and influences cerebral spinal fluid (CSF) APOE- and APOA1 levels. Together with APOE and the cholesterol transporter ABCA1, plays a key role in the maturation of glial-derived, nascent lipoproteins. Required for remodeling high-density lipoprotein particles into their spherical forms (PubMed:10722751). {ECO:0000269|PubMed:10329423, ECO:0000269|PubMed:10722751, ECO:0000269|PubMed:14636062, ECO:0000269|PubMed:19065001, ECO:0000269|PubMed:26195816, ECO:0000269|PubMed:8820107}.;
Disease
DISEASE: Lecithin-cholesterol acyltransferase deficiency (LCATD) [MIM:245900]: A disorder of lipoprotein metabolism characterized by inadequate esterification of plasmatic cholesterol. Two clinical forms are recognized: complete LCAT deficiency and fish- eye disease. LCATD is generally referred to the complete form which is associated with absence of both alpha and beta LCAT activities resulting in esterification anomalies involving both HDL (alpha-LCAT activity) and LDL (beta-LCAT activity). It causes a typical triad of diffuse corneal opacities, target cell hemolytic anemia, and proteinuria with renal failure. {ECO:0000269|PubMed:11423760, ECO:0000269|PubMed:12957688, ECO:0000269|PubMed:15994445, ECO:0000269|PubMed:16051254, ECO:0000269|PubMed:16216249, ECO:0000269|PubMed:1681161, ECO:0000269|PubMed:1859405, ECO:0000269|PubMed:2370048, ECO:0000269|PubMed:7607641, ECO:0000269|PubMed:7711728, ECO:0000269|PubMed:8318557, ECO:0000269|PubMed:8432868, ECO:0000269|PubMed:8807342, ECO:0000269|PubMed:9007616, ECO:0000269|PubMed:9741700}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Fish-eye disease (FED) [MIM:136120]: A disorder of lipoprotein metabolism due to partial lecithin-cholesterol acyltransferase deficiency that affects only alpha-LCAT activity. FED is characterized by low plasma HDL and corneal opacities due to accumulation of cholesterol deposits in the cornea ('fish- eye'). {ECO:0000269|PubMed:1516702, ECO:0000269|PubMed:1571050, ECO:0000269|PubMed:15994445, ECO:0000269|PubMed:1737840, ECO:0000269|PubMed:21901787, ECO:0000269|PubMed:8620346, ECO:0000269|PubMed:9261271}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.110

Intolerance Scores

LoFtool
0.127
RVIS EVS
-0.29
RVIS percentile EVS
32.94

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.995

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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