LRP1
protein-codingLDL receptor related protein 1, the group of CD molecules|Low density lipoprotein receptors|MicroRNA protein coding host genes
Gene summary
This gene encodes a member of the low-density lipoprotein receptor family of proteins. The encoded preproprotein is proteolytically processed by furin to generate 515 kDa and 85 kDa subunits that form the mature receptor (PMID: 8546712). This receptor is involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the alpha 2-macroglobulin-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients. Expression of this gene decreases with age and has been found to be lower than controls in brain tissue from Alzheimer's disease patients. [provided by RefSeq, Oct 2015]
- APR
- A2MR
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~84.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008849
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0018855
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0005090
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0018855
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0000136
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0958037
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0958037
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LRP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002332.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 10 | 141 | 24 | 175 | ||
| missense | 4 | 516 | 29 | 4 | 553 | |
| nonsense | 1 | 11 | 12 | |||
| start loss | 0 | |||||
| frameshift | 2 | 16 | 1 | 19 | ||
| splice donor/acceptor (+/-2bp) | 2 | 30 | 32 | |||
| Total | 6 | 3 | 583 | 171 | 28 | 791 |
Highest pathogenic variant AF is 0.00007012015
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002323.2 | 89 | MANE Select | |
| Ensembl | ENSP00000243077.3 | 89 | MANE Select | |
| Ensembl | ENSP00000341264.4 | 7 | Standard | |
| Ensembl | ENSP00000341264.4 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| lrp1aa | Danio rerio | Structure: vasculature Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Alzheimer,s disease - Homo sapiens (human)
- Malaria - Homo sapiens (human)
- Cholesterol metabolism - Homo sapiens (human)
- Statin Pathway, Pharmacodynamics
- miR-targeted genes in epithelium - TarBase
Biological Process
- retinoid metabolic process
- astrocyte activation involved in immune response
- lipid metabolic process
- receptor-mediated endocytosis
- phagocytosis
Molecular Function
- amyloid-beta binding
- protease binding
- RNA binding
- low-density lipoprotein particle receptor activity
- scavenger receptor activity
Cellular Component
- nucleus
- lysosomal membrane
- early endosome
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000243077
- Coding exons
- 89
- Length
- 84859
- Individuals with no LoFs
- 125735
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 13
- Defined
- 125748
- p
- 0.0000517
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 8.25 | 1692 | 2.95e+3 | 0.573 | 0.000209 | 30166 |
| Missense (PolyPhen) | 547 | 1378.5 | 0.39682 | 14033 | ||
| Synonymous | 2.22 | 1104 | 1.20e+3 | 0.918 | 0.0000908 | 8584 |
| Loss of Function | 14.1 | 8 | 247 | 0.0324 | 0.0000134 | 2549 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Endocytic receptor involved in endocytosis and in phagocytosis of apoptotic cells. Required for early embryonic development. Involved in cellular lipid homeostasis. Involved in the plasma clearance of chylomicron remnants and activated LRPAP1 (alpha 2-macroglobulin), as well as the local metabolism of complexes between plasminogen activators and their endogenous inhibitors. May modulate cellular events, such as APP metabolism, kinase-dependent intracellular signaling, neuronal calcium signaling as well as neurotransmission (PubMed:11907044, PubMed:12888553, PubMed:12713657). Acts as an alpha-2- macroglobulin receptor (PubMed:26142438). {ECO:0000269|PubMed:11907044, ECO:0000269|PubMed:12713657, ECO:0000269|PubMed:12888553, ECO:0000269|PubMed:26142438}.;
- Disease
- DISEASE: Keratosis pilaris atrophicans (KPA) [MIM:604093]: A group of rare genodermatoses characterized by keratotic follicular papules, variable degrees of inflammation, and secondary atrophic scarring. Most cases are associated with an atopic diathesis and keratosis pilaris on the extensor extremities. KPA is comprised of three distinct clinical subtypes: keratosis pilaris atrophicans faciei, atrophoderma vermiculatum, and keratosis follicularis spinulosa decalvans. Affected individuals may present with features overlapping the 3 subtypes. {ECO:0000269|PubMed:26142438}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.766
Intolerance Scores
- LoFtool
- 0.00262
- RVIS EVS
- -7.28
- RVIS percentile EVS
- 0.02
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.745
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |