LDLR |
- 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
- 1.09(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 low density lipoprotein /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. Forms a ternary complex with PGRMC1 and TMEM97 receptors which increases LDLR-mediated LDL internalization (PubMed:30443021). {ECO:0000269|PubMed:3005267, ECO:0000269|PubMed:30443021, ECO:0000269|PubMed:6091915}. (Microbial infection) Acts as a receptor for h... (Source: Uniprot)
Dosage Sensitivity Summary (Gene)
Dosage ID:
ISCA-18075
ClinGen Curation ID:
CCID:007395
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)