LDLR
low density lipoprotein receptor, the group of Low density lipoprotein receptors|MicroRNA protein coding host genes
Basic information
Region (hg38): 19:11089461-11133820
Links
Phenotypes
GenCC
Source:
- hypercholesterolemia, familial, 1 (Strong), mode of inheritance: AD
- homozygous familial hypercholesterolemia (Supportive), mode of inheritance: AR
- hypercholesterolemia, familial, 1 (Definitive), mode of inheritance: AD
- hypercholesterolemia, familial, 1 (Strong), mode of inheritance: AD
- hypercholesterolemia, familial, 1 (Definitive), mode of inheritance: Semidominant
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Hypercholesterolemia, familial 1 | AD/AR | Cardiovascular | Dietary and medical measures (eg, with statins) to lower cholesterol levels may be beneficial, with evidence that early diagnosis and management improves outcomes; In severe instances, therapy may include plasma apharesis, and gene therapy has been described; In Hypercholesterolemia, familial, 1, medical management (with inclisiran, a small interfering RNA), has shown evidence of benefit related to parameters such as LDL levels | Cardiovascular | 3020025; 3155573; 3924410; 3012527; 3549308; 3815525; 3818645; 3343347; 2837085; 3263645; 2563635; 2569482; 2544509; 2088165; 1978682; 1999337; 1863993; 1609792; 1734722; 8098448; 8054972; 9016531; 9645910; 10422803; 11246453; 10631147; 10882754; 11453971; 11600564; 11298688; 15657370; 17335829; 17215532; 18400033; 18354102; 20703241; 20686565; 21722902; 21872251; 21925044; 22244043; 22698793; 22881376; 22893714; 23054246; 32187462; 32197277 |
ClinVar
This is a list of variants' phenotypes submitted to
- Hypercholesterolemia, familial, 1 (2245 variants)
- Familial hypercholesterolemia (1904 variants)
- Cardiovascular phenotype (744 variants)
- not provided (547 variants)
- not specified (187 variants)
- Homozygous familial hypercholesterolemia (60 variants)
- Hypercholesterolemia (44 variants)
- LDLR-related condition (31 variants)
- Inborn genetic diseases (26 variants)
- - (4 variants)
- See cases (4 variants)
- Smith-Lemli-Opitz syndrome (2 variants)
- Early-onset coronary artery disease (2 variants)
- Familial type 3 hyperlipoproteinemia (2 variants)
- Hypercholesterolemia, autosomal dominant, type B (1 variants)
- Syndromic X-linked intellectual disability Najm type (1 variants)
- Autosomal dominant familial hypercholesterolemia (1 variants)
- Stroke disorder;Carotid artery occlusion;Carotid artery dissection;Aortic dissection;Internal carotid artery dissection (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the LDLR gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 407 | 428 | ||||
| missense | 59 | 575 | 545 | 45 | 1229 | |
| nonsense | 171 | 35 | 206 | |||
| start loss | 8 | |||||
| frameshift | 457 | 48 | 511 | |||
| inframe indel | 13 | 59 | 28 | 100 | ||
| splice donor/acceptor (+/-2bp) | 55 | 94 | 152 | |||
| splice region ? | 1 | 14 | 44 | 65 | 3 | 127 |
| non coding ? | 103 | 168 | 49 | 328 | ||
| Total | 760 | 827 | 692 | 620 | 63 |
Highest pathogenic variant AF is 0.0000591
Variants in LDLR
This is a list of pathogenic ClinVar variants found in the LDLR region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 19-11089469-T-C | Hypercholesterolemia, familial, 1 | Uncertain significance (Apr 03, 2023) | ||
| 19-11089472-CG-C | Familial hypercholesterolemia | Uncertain significance (Sep 24, 2023) | ||
| 19-11089481-A-C | Hypercholesterolemia, familial, 1 | Uncertain significance (Mar 25, 2016) | ||
| 19-11089486-T-C | Hypercholesterolemia, familial, 1 | Uncertain significance (May 16, 2023) | ||
| 19-11089493-T-C | Familial hypercholesterolemia | Uncertain significance (Nov 06, 2023) | ||
| 19-11089493-TAGGA-T | Familial hypercholesterolemia • Hypercholesterolemia, familial, 1 | Uncertain significance (Feb 05, 2024) | ||
| 19-11089501-A-G | Familial hypercholesterolemia | Uncertain significance (Jun 28, 2023) | ||
| 19-11089503-C-A | Hypercholesterolemia, familial, 1 | Uncertain significance (Dec 18, 2023) | ||
| 19-11089504-A-T | Familial hypercholesterolemia | Uncertain significance (Oct 15, 2020) | ||
| 19-11089513-T-A | Hypercholesterolemia, familial, 1 | Uncertain significance (May 04, 2023) | ||
| 19-11089513-T-G | Hypercholesterolemia, familial, 1 | Conflicting classifications of pathogenicity (Mar 25, 2016) | ||
| 19-11089521-G-C | Hypercholesterolemia, familial, 1 | Likely benign (Mar 30, 2017) | ||
| 19-11089523-G-T | Familial hypercholesterolemia | Uncertain significance (May 25, 2023) | ||
| 19-11089524-A-T | Hypercholesterolemia, familial, 1 | Uncertain significance (May 04, 2023) | ||
| 19-11089526-A-C | Hypercholesterolemia, familial, 1 • Familial hypercholesterolemia | Uncertain significance (May 02, 2023) | ||
| 19-11089526-A-G | Familial hypercholesterolemia • Hypercholesterolemia, familial, 1 | Uncertain significance (Nov 02, 2023) | ||
| 19-11089526-AC-A | Hypercholesterolemia, familial, 1 | Uncertain significance (Mar 25, 2016) | ||
| 19-11089527-C-T | Familial hypercholesterolemia | Uncertain significance (Jun 15, 2022) | ||
| 19-11089531-C-T | Hypercholesterolemia, familial, 1 | Uncertain significance (May 16, 2023) | ||
| 19-11089535-C-A | Hypercholesterolemia, familial, 1 • Familial hypercholesterolemia | Uncertain significance (Sep 23, 2019) | ||
| 19-11089536-A-G | Hypercholesterolemia, familial, 1 • Familial hypercholesterolemia • LDLR-related disorder | Benign/Likely benign (Aug 30, 2023) | ||
| 19-11089541-C-A | Hypercholesterolemia, familial, 1 | Uncertain significance (Apr 08, 2021) | ||
| 19-11089544-C-T | Hypercholesterolemia, familial, 1 | Uncertain significance (Mar 25, 2016) | ||
| 19-11089545-G-A | Hypercholesterolemia, familial, 1 | Uncertain significance (Dec 18, 2023) | ||
| 19-11089548-CATGGGGCCCTGGGGCTGGAAATTGCGCTGGACCGTCGCCTTGCTCCTCGCCGCGGCGGGGACTGCAG-C | Pathogenic (Nov 02, 2021) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| LDLR | protein_coding | protein_coding | ENST00000558518 | 18 | 44455 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 9.84e-24 | 0.00696 | 125659 | 1 | 88 | 125748 | 0.000354 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 0.124 | 505 | 513 | 0.985 | 0.0000351 | 5729 |
| Missense in Polyphen | 184 | 194.02 | 0.94834 | 2266 | ||
| Synonymous | -1.12 | 243 | 222 | 1.10 | 0.0000185 | 1598 |
| Loss of Function | 0.848 | 39 | 45.2 | 0.864 | 0.00000228 | 489 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000329 | 0.000325 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000326 | 0.000326 |
| Finnish | 0.000324 | 0.000323 |
| European (Non-Finnish) | 0.000458 | 0.000448 |
| Middle Eastern | 0.000326 | 0.000326 |
| South Asian | 0.000523 | 0.000490 |
| Other | 0.000163 | 0.000163 |
dbNSFP
Source:
- Function
- 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}.; FUNCTION: (Microbial infection) Acts as a receptor for Vesicular stomatitis virus. {ECO:0000269|PubMed:23589850}.;
- Disease
- DISEASE: Familial hypercholesterolemia (FH) [MIM:143890]: A common autosomal dominant disorder characterized by elevated serum low- density lipoprotein (LDL) cholesterol levels, which result in excess deposition of cholesterol in tissues and leads to xanthelasma, xanthomas, accelerated atherosclerosis and increased risk of premature coronary heart disease. The disorder occurs in 2 clinical forms: a mild form that becomes evident in the fourth or fifth decade in individuals carrying heterozygous LDLR mutations; a more severe form that usually manifests in the first two decades of life in individuals with homozygous LDLR mutations. {ECO:0000269|PubMed:10090484, ECO:0000269|PubMed:10206683, ECO:0000269|PubMed:10422803, ECO:0000269|PubMed:10447263, ECO:0000269|PubMed:10532689, ECO:0000269|PubMed:10660340, ECO:0000269|PubMed:10882754, ECO:0000269|PubMed:10978268, ECO:0000269|PubMed:10980548, ECO:0000269|PubMed:11298688, ECO:0000269|PubMed:11462246, ECO:0000269|PubMed:1446662, ECO:0000269|PubMed:1464748, ECO:0000269|PubMed:17142622, ECO:0000269|PubMed:17347910, ECO:0000269|PubMed:1867200, ECO:0000269|PubMed:19318025, ECO:0000269|PubMed:19319977, ECO:0000269|PubMed:22160468, ECO:0000269|PubMed:22509010, ECO:0000269|PubMed:2318961, ECO:0000269|PubMed:24529145, ECO:0000269|PubMed:25378237, ECO:0000269|PubMed:25545329, ECO:0000269|PubMed:2569482, ECO:0000269|PubMed:2726768, ECO:0000269|PubMed:3263645, ECO:0000269|PubMed:3955657, ECO:0000269|PubMed:7550239, ECO:0000269|PubMed:7573037, ECO:0000269|PubMed:7583548, ECO:0000269|PubMed:7635461, ECO:0000269|PubMed:7635482, ECO:0000269|PubMed:7649546, ECO:0000269|PubMed:7649549, ECO:0000269|PubMed:8168830, ECO:0000269|PubMed:8347689, ECO:0000269|PubMed:8462973, ECO:0000269|PubMed:8664907, ECO:0000269|PubMed:8740918, ECO:0000269|PubMed:9026534, ECO:0000269|PubMed:9104431, ECO:0000269|PubMed:9143924, ECO:0000269|PubMed:9254862, ECO:0000269|PubMed:9259195, ECO:0000269|PubMed:9452094, ECO:0000269|PubMed:9452095, ECO:0000269|PubMed:9452118, ECO:0000269|PubMed:9654205, ECO:0000269|PubMed:9678702, ECO:0000269|PubMed:9852677, ECO:0000269|Ref.71}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Cortisol synthesis and secretion - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Endocytosis - Homo sapiens (human);Bile secretion - Homo sapiens (human);Cholesterol metabolism - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Ovarian steroidogenesis - Homo sapiens (human);Statin Pathway, Pharmacodynamics;Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate Metabolism;Sterol Regulatory Element-Binding Proteins (SREBP) signalling;SREBF and miR33 in cholesterol and lipid homeostasis;Oncostatin M Signaling Pathway;Proprotein convertase subtilisin-kexin type 9 (PCSK9) mediated LDL receptor degradation;Evolocumab Mechanism;Composition of Lipid Particles;Wnt Signaling Pathway and Pluripotency;Liver steatosis AOP;Statin Pathway;DNA Damage Response (only ATM dependent);Signaling by GPCR;Signal Transduction;Metabolism of fat-soluble vitamins;Vesicle-mediated transport;Membrane Trafficking;Chylomicron clearance;Metabolism;LDL clearance;Plasma lipoprotein clearance;Transport of small molecules;Metabolism of vitamins and cofactors;Clathrin-mediated endocytosis;EGFR1;srebp control of lipid synthesis;Plasma lipoprotein assembly, remodeling, and clearance;Retinoid metabolism and transport;Cargo recognition for clathrin-mediated endocytosis;G alpha (i) signalling events;Visual phototransduction;GPCR downstream signalling
(Consensus)
Recessive Scores
- pRec
- 0.943
Intolerance Scores
- loftool
- 0.0737
- rvis_EVS
- -1.85
- rvis_percentile_EVS
- 2.03
Haploinsufficiency Scores
- pHI
- 0.426
- hipred
- N
- hipred_score
- 0.486
- ghis
- 0.538
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- E
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.965
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Ldlr
- Phenotype
- vision/eye phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); immune system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); pigmentation phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region phenotype; normal phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan);
Zebrafish Information Network
- Gene name
- ldlra
- Affected structure
- blood plasma
- Phenotype tag
- abnormal
- Phenotype quality
- decreased amount
Gene ontology
- Biological process
- lipid metabolic process;endocytosis;receptor-mediated endocytosis;long-term memory;cholesterol metabolic process;positive regulation of gene expression;negative regulation of gene expression;positive regulation of triglyceride biosynthetic process;regulation of phosphatidylcholine catabolic process;positive regulation of lipoprotein particle clearance;phospholipid transport;intestinal cholesterol absorption;cholesterol transport;plasma lipoprotein particle clearance;chylomicron remnant clearance;low-density lipoprotein particle clearance;high-density lipoprotein particle clearance;lipoprotein catabolic process;cholesterol homeostasis;positive regulation of endocytosis;viral entry into host cell;positive regulation of inflammatory response;regulation of protein metabolic process;negative regulation of protein metabolic process;membrane organization;response to caloric restriction;negative regulation of astrocyte activation;cholesterol import;cellular response to fatty acid;cellular response to low-density lipoprotein particle stimulus;receptor-mediated endocytosis involved in cholesterol transport;regulation of cholesterol metabolic process;amyloid-beta clearance;positive regulation of amyloid-beta clearance;negative regulation of microglial cell activation;positive regulation of lysosomal protein catabolic process;negative regulation of amyloid fibril formation
- Cellular component
- lysosome;early endosome;late endosome;Golgi apparatus;plasma membrane;integral component of plasma membrane;clathrin-coated pit;external side of plasma membrane;cell surface;endosome membrane;membrane;basolateral plasma membrane;clathrin-coated endocytic vesicle membrane;low-density lipoprotein particle;endolysosome membrane;somatodendritic compartment;receptor complex;apical part of cell;sorting endosome;PCSK9-LDLR complex
- Molecular function
- amyloid-beta binding;virus receptor activity;protease binding;low-density lipoprotein particle receptor activity;calcium ion binding;protein binding;low-density lipoprotein particle binding;very-low-density lipoprotein particle receptor activity;clathrin heavy chain binding;identical protein binding