LRP8
protein-codingLDL receptor related protein 8, the group of Low density lipoprotein receptors
Gene summary
This gene encodes a member of the low density lipoprotein receptor (LDLR) family. Low density lipoprotein receptors are cell surface proteins that play roles in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation. The encoded protein plays a critical role in the migration of neurons during development by mediating Reelin signaling, and also functions as a receptor for the cholesterol transport protein apolipoprotein E. Expression of this gene may be a marker for major depressive disorder. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~86.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0007661
Submitter: Labcorp Genetics (formerly Invitae)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LRP8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004631.5. 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 | 2 | 5 | 7 | 14 | ||
| missense | 117 | 10 | 127 | |||
| nonsense | 4 | 4 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | 4 | |||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 127 | 17 | 7 | 151 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004622.2 | 19 | MANE Select | |
| Ensembl | ENSP00000303634.6 | 19 | MANE Select | |
| RefSeq | NP_001018064.1 | 18 | Standard | |
| RefSeq | NP_059992.3 | 16 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signaling by GPCR
- Signal Transduction
- Metabolism of fat-soluble vitamins
- lissencephaly gene (lis1) in neuronal migration and development
- Metabolism
Biological Process
- negative regulation of transcription by RNA polymerase II
- retinoid metabolic process
- proteolysis
- lipid metabolic process
- endocytosis
Molecular Function
- transmembrane signaling receptor activity
- low-density lipoprotein particle receptor activity
- calcium ion binding
- protein binding
- high-density lipoprotein particle binding
Cellular Component
- extracellular region
- microtubule associated complex
- plasma membrane
- caveola
- postsynaptic density
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000306052
- Coding exons
- 19
- Length
- 82526
- Individuals with no LoFs
- 125737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125748
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.52 | 382 | 548 | 0.697 | 0.0000335 | 6293 |
| Missense (PolyPhen) | 147 | 251.17 | 0.58526 | 2776 | ||
| Synonymous | 1.45 | 197 | 225 | 0.877 | 0.0000154 | 1842 |
| Loss of Function | 5.67 | 5 | 46.9 | 0.107 | 0.00000234 | 529 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00012 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000026 | 0.000026 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cell surface receptor for Reelin (RELN) and apolipoprotein E (apoE)-containing ligands. LRP8 participates in transmitting the extracellular Reelin signal to intracellular signaling processes, by binding to DAB1 on its cytoplasmic tail. Reelin acts via both the VLDL receptor (VLDLR) and LRP8 to regulate DAB1 tyrosine phosphorylation and microtubule function in neurons. LRP8 has higher affinity for Reelin than VLDLR. LRP8 is thus a key component of the Reelin pathway which governs neuronal layering of the forebrain during embryonic brain development. Binds the endoplasmic reticulum resident receptor-associated protein (RAP). Binds dimers of beta 2-glycoprotein I and may be involved in the suppression of platelet aggregation in the vasculature. Highly expressed in the initial segment of the epididymis, where it affects the functional expression of clusterin and phospholipid hydroperoxide glutathione peroxidase (PHGPx), two proteins required for sperm maturation. May also function as an endocytic receptor. Not required for endocytic uptake of SEPP1 in the kidney which is mediated by LRP2 (By similarity). {ECO:0000250|UniProtKB:Q924X6, ECO:0000269|PubMed:12807892, ECO:0000269|PubMed:12899622, ECO:0000269|PubMed:12950167}.;
- Disease
- DISEASE: Myocardial infarction 1 (MCI1) [MIM:608446]: A condition defined by the irreversible necrosis of heart muscle secondary to prolonged ischemia. {ECO:0000269|PubMed:17847002}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.265
Intolerance Scores
- LoFtool
- 0.0113
- RVIS EVS
- -0.88
- RVIS percentile EVS
- 10.5
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.681
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |