LRP5

LDL receptor related protein 5, the group of Low density lipoprotein receptors

Basic information

Region (hg38): 11:68312590-68449275

Previous symbols: [ "LRP7", "OPPG", "EVR1" ]

Links

ENSG00000162337 ∙ NCBI:4041 ∙ OMIM:603506 ∙ HGNC:6697 ∙ Uniprot:O75197 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant osteopetrosis 1 (Definitive), mode of inheritance: AD
• autosomal dominant osteosclerosis, Worth type (Definitive), mode of inheritance: AD
• exudative vitreoretinopathy 4 (Definitive), mode of inheritance: AD
• osteoporosis-pseudoglioma syndrome (Definitive), mode of inheritance: AR
• polycystic liver disease 4 with or without kidney cysts (Strong), mode of inheritance: AD
• autosomal dominant osteosclerosis, Worth type (Strong), mode of inheritance: AD
• exudative vitreoretinopathy 4 (Definitive), mode of inheritance: Semidominant
• autosomal dominant osteopetrosis 1 (Moderate), mode of inheritance: AD
• osteoporosis-pseudoglioma syndrome (Definitive), mode of inheritance: AR
• autosomal dominant osteopetrosis 1 (Supportive), mode of inheritance: AD
• osteoporosis-pseudoglioma syndrome (Supportive), mode of inheritance: AR
• autosomal dominant osteosclerosis, Worth type (Supportive), mode of inheritance: AD
• polycystic liver disease 1 (Supportive), mode of inheritance: AD
• hyperostosis corticalis generalisata (Supportive), mode of inheritance: AD
• exudative vitreoretinopathy (Supportive), mode of inheritance: AD
• osteosclerosis-developmental delay-craniosynostosis syndrome (Supportive), mode of inheritance: AD
• exudative vitreoretinopathy 4 (Strong), mode of inheritance: Unknown
• bone mineral density quantitative trait locus 1 (Definitive), mode of inheritance: AD
• autosomal dominant osteosclerosis, Worth type (Strong), mode of inheritance: AD
• osteoporosis-pseudoglioma syndrome (Strong), mode of inheritance: AR
• exudative vitreoretinopathy 4 (Strong), mode of inheritance: AD
• polycystic liver disease 4 with or without kidney cysts (Strong), mode of inheritance: AD
• inherited retinal dystrophy (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
van Buchem disease, type 2; Osteopetrosis, autosomal dominant 1; Polycystic liver disease 4 with or without kidney cysts; Endosteal hyperostosis, autosomal dominant; Exudative vitreoretinopathy 4; Osteoporosis-pseudoglioma syndrome	AD/AR/Digenic	General	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	Gastrointestinal; Musculoskeletal; Ophthalmologic; Renal	8832721; 9056564; 9831343; 10434540; 11719191; 12015390; 11741193; 12054167; 12579474; 15346351; 15024691; 15981244; 20301326; 21407258; 21600326; 22456437; 22487062; 23077402; 25920554
Digenic inheritance (with FZD4) has been reported in Exudative vitreoretinopathy

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LRP5 gene.

• not provided (1738 variants)
• 8 conditions (251 variants)
• not specified (68 variants)
• Osteogenesis imperfecta (68 variants)
• Inborn genetic diseases (59 variants)
• Osteoporosis with pseudoglioma (23 variants)
• Exudative vitreoretinopathy 4 (20 variants)
• LRP5-related condition (13 variants)
• Increased bone mineral density (10 variants)
• Autosomal dominant polycystic liver disease (9 variants)
• Retinal dystrophy (9 variants)
• Polycystic liver disease 4 with or without kidney cysts (6 variants)
• Bone mineral density quantitative trait locus 1 (4 variants)
• Polycystic kidney disease, adult type (4 variants)
• Autosomal dominant osteopetrosis 1 (3 variants)
• Exudative vitreoretinopathy 1 (3 variants)
• Familial exudative vitreoretinopathy (3 variants)
• Exudative vitreoretinopathy 4, autosomal recessive (3 variants)
• Postmenopausal osteoporosis (2 variants)
• Microcephaly (2 variants)
• Osteoporosis (2 variants)
• 9 conditions (2 variants)
• Polycystic liver disease 1 (2 variants)
• Worth disease (2 variants)
• Exudative vitreoretinopathy 4, digenic (1 variants)
• Exudative vitreoretinopathy 4;Osteoporosis with pseudoglioma;Autosomal dominant osteopetrosis 1;Polycystic liver disease 1 (1 variants)
• 7 conditions (1 variants)
• See cases (1 variants)
• Autosomal dominant polycystic kidney disease (1 variants)
• Leber congenital amaurosis (1 variants)
• 6 conditions (1 variants)
• High bone mass (1 variants)
• LRP5-related primary osteoporosis (1 variants)
• Exudative vitreoretinopathy 4, autosomal dominant (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LRP5 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			13	424	19	456
missense	15	36	737	16	5	809
nonsense	18	6				24
start loss		1				1
frameshift	36	7	1			44
inframe indel			26	3	1	30
splice donor/acceptor (+/-2bp)	6	12				18
splice region		1	34	32	4	71
non coding			11	188	68	267
Total	75	62	788	631	93

Highest pathogenic variant AF is 0.0000662

Variants in LRP5

This is a list of pathogenic ClinVar variants found in the LRP5 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-68312693-GC-G		not specified	Conflicting classifications of pathogenicity (Apr 01, 2023)
11-68312707-C-T			Uncertain significance (Dec 03, 2015)
11-68312715-A-G		Osteogenesis imperfecta	Pathogenic/Likely pathogenic (Jan 12, 2024)
11-68312715-A-T			Pathogenic (Aug 14, 2023)
11-68312723-A-T			Uncertain significance (Dec 03, 2015)
11-68312725-C-G			Uncertain significance (Jan 01, 2023)
11-68312726-G-A			Uncertain significance (Dec 03, 2015)
11-68312727-C-G			Uncertain significance (May 27, 2022)
11-68312728-C-T			Uncertain significance (Dec 03, 2015)
11-68312729-G-C			Likely benign (Apr 21, 2022)
11-68312730-C-A		not specified • Osteogenesis imperfecta	Benign/Likely benign (Jan 29, 2024)
11-68312732-C-T			Likely benign (Jan 24, 2024)
11-68312733-G-C			Uncertain significance (Jul 03, 2022)
11-68312736-C-A			Uncertain significance (Dec 01, 2023)
11-68312743-G-A		Osteoporosis with pseudoglioma	Pathogenic (Nov 16, 2001)
11-68312742-T-TGGCCGCTGC			Uncertain significance (Dec 01, 2023)
11-68312745-C-T		Inborn genetic diseases	Uncertain significance (Nov 13, 2023)
11-68312746-CGCT-C		not specified	Benign/Likely benign (Jan 16, 2024)
11-68312746-CGCTGCT-C		Osteogenesis imperfecta	Conflicting classifications of pathogenicity (Jan 29, 2024)
11-68312746-CGCTGCTGCT-C		not specified • Autosomal dominant polycystic liver disease • Increased bone mineral density • Osteogenesis imperfecta	Benign/Likely benign (Mar 01, 2024)
11-68312746-CGCTGCTGCTGCT-C			Uncertain significance (Aug 04, 2023)
11-68312746-CGCTGCTGCTGCTGCT-C		8 conditions	Uncertain significance (Dec 17, 2023)
11-68312746-C-CGCT		not specified • Exudative vitreoretinopathy 4	Benign (Jan 31, 2024)
11-68312746-C-CGCTGCT		not specified • Osteogenesis imperfecta • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 29, 2024)
11-68312746-C-CGCTGCTGCT			Uncertain significance (Dec 13, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LRP5	protein_coding	protein_coding	ENST00000294304	23	136667

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.510	0.490	125709	0	39	125748	0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.67	946	1.10e+3	0.859	0.0000833	10542
Missense in Polyphen		289	405.56	0.71259		3778
Synonymous	-1.15	541	508	1.06	0.0000442	3275
Loss of Function	5.94	15	67.8	0.221	0.00000346	713

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000429	0.000427
Ashkenazi Jewish	0.000500	0.000496
East Asian	0.000163	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.000169	0.000167
Middle Eastern	0.000163	0.000163
South Asian	0.0000989	0.0000980
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins (PubMed:11336703, PubMed:11448771, PubMed:15778503, PubMed:11719191, PubMed:15908424, PubMed:16252235). Activates the canonical Wnt signaling pathway that controls cell fate determination and self-renewal during embryonic development and adult tissue regeneration (PubMed:11336703, PubMed:11719191). In particular, may play an important role in the development of the posterior patterning of the epiblast during gastrulation (By similarity). During bone development, regulates osteoblast proliferation and differentiation thus determining bone mass (PubMed:11719191). Mechanistically, the formation of the signaling complex between Wnt ligand, frizzled receptor and LRP5 coreceptor promotes the recruitment of AXIN1 to LRP5, stabilizing beta- catenin/CTNNB1 and activating TCF/LEF-mediated transcriptional programs (PubMed:11336703, PubMed:25920554, PubMed:24706814, PubMed:14731402). Acts as a coreceptor for non-Wnt proteins, such as norrin/NDP. Binding of norrin/NDP to frizzled 4/FZD4-LRP5 receptor complex triggers beta-catenin/CTNNB1-dependent signaling known to be required for retinal vascular development (PubMed:27228167, PubMed:16252235). Plays a role in controlling postnatal vascular regression in retina via macrophage-induced endothelial cell apoptosis (By similarity). {ECO:0000250|UniProtKB:Q91VN0, ECO:0000269|PubMed:11336703, ECO:0000269|PubMed:11448771, ECO:0000269|PubMed:11719191, ECO:0000269|PubMed:14731402, ECO:0000269|PubMed:15778503, ECO:0000269|PubMed:15908424, ECO:0000269|PubMed:16252235, ECO:0000269|PubMed:24706814, ECO:0000269|PubMed:25920554, ECO:0000269|PubMed:27228167}.
• Disease: DISEASE: Vitreoretinopathy, exudative 1 (EVR1) [MIM:133780]: A disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. In many ways the disease resembles retinopathy of prematurity but there is no evidence of prematurity or small birth weight in the patient history. {ECO:0000269|PubMed:27228167}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Vitreoretinopathy, exudative 4 (EVR4) [MIM:601813]: A disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. {ECO:0000269|PubMed:15024691, ECO:0000269|PubMed:15346351, ECO:0000269|PubMed:15981244, ECO:0000269|PubMed:16252235, ECO:0000269|PubMed:16929062, ECO:0000269|PubMed:19324841, ECO:0000269|PubMed:20340138, ECO:0000269|PubMed:24715757}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteoporosis (OSTEOP) [MIM:166710]: A systemic skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture without alteration in the composition of bone. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. {ECO:0000269|PubMed:14727154, ECO:0000269|PubMed:15824851, ECO:0000269|PubMed:16234968}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Osteoporosis-pseudoglioma syndrome (OPPG) [MIM:259770]: A disease characterized by congenital or infancy-onset blindness and severe juvenile-onset osteoporosis and spontaneous fractures. Additional clinical manifestations may include microphthalmos, abnormalities of the iris, lens or vitreous, cataracts, short stature, microcephaly, ligamental laxity, mental retardation and hypotonia. {ECO:0000269|PubMed:11719191, ECO:0000269|PubMed:16252235, ECO:0000269|PubMed:16679074, ECO:0000269|PubMed:17437160, ECO:0000269|PubMed:18602879}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: High bone mass trait (HBM) [MIM:601884]: Rare phenotype characterized by exceptionally dense bones. HBM individuals show otherwise a completely normal skeletal structure and no other unusual clinical findings. {ECO:0000269|PubMed:11741193, ECO:0000269|PubMed:12015390, ECO:0000269|PubMed:15143163, ECO:0000269|PubMed:15824861, ECO:0000269|PubMed:17295608}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Endosteal hyperostosis, Worth type (WENHY) [MIM:144750]: An autosomal dominant sclerosing bone dysplasia clinically characterized by elongation of the mandible, increased gonial angle, flattened forehead, and the presence of a slowly enlarging osseous prominence of the hard palate (torus palatinus). Serum calcium, phosphorus and alkaline phosphatase levels are normal. Radiologically, it is characterized by early thickening of the endosteum of long bones, the skull and of the mandible. With advancing age, the trabeculae of the metaphysis become thickened. WENHY becomes clinically and radiologically evident by adolescence, does not cause deformity except in the skull and mandible, and is not associated with bone pain or fracture. Affected patients have normal height, proportion, intelligence and longevity. {ECO:0000269|PubMed:12579474}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteopetrosis, autosomal dominant 1 (OPTA1) [MIM:607634]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. OPTA1 is an autosomal dominant form characterized by generalized osteosclerosis most pronounced in the cranial vault. Patients are often asymptomatic, but some suffer from pain and hearing loss. It appears to be the only type of osteopetrosis not associated with an increased fracture rate. {ECO:0000269|PubMed:12579474}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Van Buchem disease 2 (VBCH2) [MIM:607636]: VBCH2 is an autosomal dominant sclerosing bone dysplasia characterized by cranial osteosclerosis, thickened calvaria and cortices of long bones, enlarged mandible and normal serum alkaline phosphatase levels. {ECO:0000269|PubMed:12579474}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Polycystic liver disease 4 with or without kidney cysts (PCLD4) [MIM:617875]: A form of polycystic liver disease, an autosomal dominant hepatobiliary disease characterized by overgrowth of biliary epithelium and supportive connective tissue, resulting in multiple liver cysts. PCLD4 patients may also develop kidney cysts that usually do not result in clinically significant renal disease. {ECO:0000269|PubMed:24706814, ECO:0000269|PubMed:28375157}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=LRP5 variations may act as a disease modifier in autosomal dominant polycystic kidney disease (ADPKD) in patients who have causative mutations in PKD1. May contribute to the disease phenotype heterogeneity and hepatic cystogenesis. {ECO:0000269|PubMed:25920554}.
• Pathway: Gastric cancer - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Breast cancer - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);WNT-Core;MicroRNAs in cardiomyocyte hypertrophy;Primary Focal Segmental Glomerulosclerosis FSGS;Hair Follicle Development- Induction (Part 1 of 3);Vitamin D Receptor Pathway;Wnt Signaling Pathway;Wnt-beta-catenin Signaling Pathway in Leukemia;ESC Pluripotency Pathways;Wnt Signaling Pathway and Pluripotency;Wnt Signaling in Kidney Disease;EMT transition in Colorectal Cancer;Wnt Signaling Pathway;Signaling by WNT;Signal Transduction;Disassembly of the destruction complex and recruitment of AXIN to the membrane;Regulation of FZD by ubiquitination;Negative regulation of TCF-dependent signaling by WNT ligand antagonists;Wnt;Wnt Canonical;Wnt signaling network;N-cadherin signaling events;TCF dependent signaling in response to WNT;Wnt Mammals (Consensus)

Recessive Scores

• pRec: 0.104

Intolerance Scores

• loftool: 0.0154
• rvis_EVS: -3.72
• rvis_percentile_EVS: 0.24

Haploinsufficiency Scores

• pHI: 0.0767
• hipred: Y
• hipred_score: 0.655
• ghis: 0.623

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.976

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Lrp5
• Phenotype: growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype; vision/eye phenotype; craniofacial phenotype; 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); normal 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); hematopoietic system phenotype; pigmentation phenotype; embryo phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton 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); limbs/digits/tail phenotype

Zebrafish Information Network

• Gene name: lrp5
• Affected structure: neuromast hair cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: gastrulation with mouth forming second;positive regulation of mesenchymal cell proliferation;osteoblast development;glucose catabolic process;endocytosis;regulation of blood pressure;positive regulation of cell population proliferation;anterior/posterior pattern specification;Wnt signaling pathway;cholesterol homeostasis;positive regulation of fat cell differentiation;negative regulation of osteoblast differentiation;positive regulation of osteoblast differentiation;positive regulation of mitotic nuclear division;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;bone remodeling;bone marrow development;retina morphogenesis in camera-type eye;canonical Wnt signaling pathway;bone morphogenesis;branching involved in mammary gland duct morphogenesis;adipose tissue development;regulation of insulin secretion involved in cellular response to glucose stimulus;retinal blood vessel morphogenesis;negative regulation of protein serine/threonine kinase activity;toxin transport
• Cellular component: endoplasmic reticulum;plasma membrane;integral component of membrane;receptor complex;Wnt-Frizzled-LRP5/6 complex;Wnt signalosome
• Molecular function: protein binding;Wnt-protein binding;toxin transmembrane transporter activity;Wnt-activated receptor activity;coreceptor activity involved in Wnt signaling pathway;coreceptor activity involved in canonical Wnt signaling pathway