• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
LDLR (HGNC:6547) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
low density lipoprotein receptor
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
LDLCQ2
%HI
17.35(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0(Read more about gnomAD pLI score)
LOEUF
1.13(Read more about gnomAD LOEUF score)
Cytoband
19p13.2
Genomic Coordinates
GRCh37/hg19: chr19:11200139-11244496 NCBI Ensembl UCSC
GRCh38/hg38: chr19:11089463-11133820 NCBI Ensembl UCSC
MANE Select Transcript
NM_000527.5 ENST00000558518.6 (Read more about MANE Select)
Function
Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. {ECO:0000269|PubMed:3005267, ECO:0000269|PubMed:6091915}. (Microbial infection) Acts as a receptor for hepatitis C virus in hepatocytes, but not through a direct interaction with viral proteins. {ECO:0000269|PubMed:10535997, ECO:0000269|PubMed:12615904}. (Microbial infection) Acts as ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-18075
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
10/27/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • hypercholesterolemia, familial, 1 Monarch
HI Evidence:
  • PUBMED: 33740630
    Leren et al. screened 29,449 unrelated hypercholesterolemic patients for variants in the LDLR, APOB, and PCSK9 genes. The authors identified 259 different disease-causing variants in the LDLR gene in affected individuals, including 123 missense, 38 small deletions or duplications, 28 nonsense, 31 variants were in the flanking introns, and 30 copy number variants identified by MLPA.
  • PUBMED: 15321837
    Austin et al. 2015 reviewed the literature to establish prevalence estimates for familial hypercholesterolemia and review variants reported in two online FH databases citing more than 700 reported in individuals with FH as of 2003. Of those 700, more than 80 are deletions and duplications, and are estimated to account for 5% of those with FH in genetically heterogeneous populations.
  • PUBMED: 20809525
    Marduel et al 2010, collected data from 1358 French probands with FH and identified 391 unique LDLR variants in 1003 individuals representing. The mutation spectrum of these variants is as follows: 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% rearrangements, 3.8% small in-frame deletions/insertions, and 1.0% UTR mutations.
HI Evidence Comments:
The LDLR gene encodes the low density lipoprotein receptor, which is important in cholesterol homeostasis. Loss of function variants in LDLR are the most common cause of familial hypercholesterolemia (FH), which is characterized by significantly increased LDL cholesterol (LDL-c) levels leading to a build up of atherosclerotic plaque in the coronary arteries increasing risk for cardiovascular disease. To date, thousands of LDLR variants have been identified in affected individuals across the mutation spectrum, including nonsense, missense, frameshift, large and small deletions and duplications (see GeneReviews). Extensive data, including functional data and animal models support loss of function as the mechanism of disease for this gene (PMIDS:189940, 2280177, 8349823, 17080197). Additionally, individuals with two pathogenic LDLR variants demonstrate a more severe phenotype with higher LDL-c levels at earlier ages supporting a semi-dominant inheritance pattern for this disease (see GeneReviews). The overall evidence that LDLR, when altered, causes hypercholesterolemia, familial, 1 has been reviewed as definitive by the ClinGen General Gene Curation Working Group.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000019.9) (NC_000019.10)