LRP2

LDL receptor related protein 2, the group of Low density lipoprotein receptors

Basic information

Region (hg38): 2:169127108-169362534

Links

ENSG00000081479 ∙ NCBI:4036 ∙ OMIM:600073 ∙ HGNC:6694 ∙ Uniprot:P98164 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability, autosomal dominant 40 (Limited), mode of inheritance: AD
• Donnai-Barrow syndrome (Definitive), mode of inheritance: AR
• Stickler syndrome (Moderate), mode of inheritance: AD
• Donnai-Barrow syndrome (Strong), mode of inheritance: AR
• Donnai-Barrow syndrome (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Donnai-Barrow syndrome; Faciooculoacousticorenal syndrome	AR	Audiologic/Otolaryngologic; General	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Ophthalmologic; Renal	8266995; 9475100; 12923867; 17632512; 18553518; 20301732

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LRP2 gene.

• not provided (3008 variants)
• Donnai-Barrow syndrome (747 variants)
• Inborn genetic diseases (188 variants)
• not specified (104 variants)
• Intellectual disability (16 variants)
• LRP2-related condition (11 variants)
• Hearing impairment (4 variants)
• DSD incomplete virilization (4 variants)
• Hearing loss and Retinal dystrophy (2 variants)
• Global developmental delay (1 variants)
• High myopia;Prolactin-producing pituitary gland adenoma (1 variants)
• Retinal dystrophy (1 variants)
• Non-syndromic syndactyly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LRP2 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			27	656	32	715
missense		4	1290	80	22	1396
nonsense	32	7				39
start loss						0
frameshift	17	7				24
inframe indel			4			4
splice donor/acceptor (+/-2bp)	3	26	2			31
splice region		1	58	95	14	168
non coding			38	432	199	669
Total	52	44	1361	1168	253

Highest pathogenic variant AF is 0.00000658

Variants in LRP2

This is a list of pathogenic ClinVar variants found in the LRP2 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-169127262-T-TCATC		Donnai-Barrow syndrome	Likely benign (Jun 14, 2016)
2-169127277-T-A		Donnai-Barrow syndrome	Uncertain significance (Jan 12, 2018)
2-169127290-T-A		Donnai-Barrow syndrome	Uncertain significance (Jun 14, 2016)
2-169127298-T-C		Donnai-Barrow syndrome	Uncertain significance (Jan 13, 2018)
2-169127441-G-A		Donnai-Barrow syndrome	Uncertain significance (Jan 13, 2018)
2-169127476-A-T		Donnai-Barrow syndrome	Uncertain significance (Jan 12, 2018)
2-169127532-C-CA		Donnai-Barrow syndrome	Uncertain significance (Jun 14, 2016)
2-169127533-T-TA		Donnai-Barrow syndrome	Uncertain significance (Jun 14, 2016)
2-169127533-T-TAA		Donnai-Barrow syndrome	Uncertain significance (Jun 14, 2016)
2-169127533-T-TAAA		Donnai-Barrow syndrome	Uncertain significance (Jun 14, 2016)
2-169127545-A-C		Donnai-Barrow syndrome	Likely benign (Jan 13, 2018)
2-169127556-C-A		Donnai-Barrow syndrome	Uncertain significance (Jan 12, 2018)
2-169127614-C-T		Donnai-Barrow syndrome	Uncertain significance (Jan 13, 2018)
2-169127666-A-G		Donnai-Barrow syndrome	Uncertain significance (Jan 12, 2018)
2-169127672-G-A		Donnai-Barrow syndrome	Uncertain significance (Jan 13, 2018)
2-169127701-A-T		Donnai-Barrow syndrome	Uncertain significance (Jan 12, 2018)
2-169127752-AT-A		Donnai-Barrow syndrome	Uncertain significance (Jun 14, 2016)
2-169127752-A-AT		Donnai-Barrow syndrome	Benign (Jun 14, 2016)
2-169127752-A-ATT		Donnai-Barrow syndrome	Uncertain significance (Jun 14, 2016)
2-169127752-A-ATTT		Donnai-Barrow syndrome	Uncertain significance (Jun 14, 2016)
2-169127839-C-A		Donnai-Barrow syndrome	Uncertain significance (Jan 12, 2018)
2-169127924-G-C		Donnai-Barrow syndrome	Likely benign (Jan 12, 2018)
2-169128031-A-T		Donnai-Barrow syndrome	Uncertain significance (Jan 13, 2018)
2-169128119-A-G		Donnai-Barrow syndrome	Benign (Jan 13, 2018)
2-169128133-G-A		Donnai-Barrow syndrome	Likely benign (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LRP2	protein_coding	protein_coding	ENST00000263816	79	235577

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000663	125661	0	87	125748	0.000346

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.07	2242	2.53e+3	0.884	0.000146	31104
Missense in Polyphen		653	1011	0.64592		12688
Synonymous	-0.779	951	921	1.03	0.0000553	8418
Loss of Function	11.6	47	241	0.195	0.0000141	2805

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000445	0.000445
Ashkenazi Jewish	0.000596	0.000595
East Asian	0.000272	0.000272
Finnish	0.000508	0.000508
European (Non-Finnish)	0.000379	0.000378
Middle Eastern	0.000272	0.000272
South Asian	0.000261	0.000261
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Multiligand endocytic receptor (By similarity). Acts together with CUBN to mediate endocytosis of high-density lipoproteins (By similarity). Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B (By similarity). In the kidney, mediates the tubular uptake and clearance of leptin (By similarity). Also mediates transport of leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium (By similarity). Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight (By similarity). Mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells (By similarity). Mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP (By similarity). Mediates renal uptake of metallothionein-bound heavy metals (PubMed:15126248). Together with CUBN, mediates renal reabsorption of myoglobin (By similarity). Mediates renal uptake and subsequent lysosomal degradation of APOM (By similarity). Plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1 (By similarity). Mediates renal uptake of the antiapoptotic protein BIRC5/survivin which may be important for functional integrity of the kidney (PubMed:23825075). Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (By similarity). Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH (By similarity). Also mediates ShhN transcytosis (By similarity). In the embryonic neuroepithelium, mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube and plays a role in patterning of the ventral telencephalon (By similarity). Required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH (By similarity). During neurulation, required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1 which is necessary for neural tube closure (By similarity). In the adult brain, negatively regulates BMP signaling in the subependymal zone which enables neurogenesis to proceed (By similarity). In astrocytes, mediates endocytosis of ALB which is required for the synthesis of the neurotrophic factor oleic acid (By similarity). Involved in neurite branching (By similarity). During optic nerve development, required for SHH- mediated migration and proliferation of oligodendrocyte precursor cells (By similarity). Mediates endocytic uptake and clearance of SHH in the retinal margin which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent (By similarity). Plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG (By similarity). Mediates endocytosis of angiotensin-2 (By similarity). Also mediates endocytosis of angiotensis 1-7 (By similarity). Binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation (By similarity). Required for embryonic heart development (By similarity). Required for normal hearing, possibly through interaction with estrogen in the inner ear (By similarity). {ECO:0000250|UniProtKB:A2ARV4, ECO:0000250|UniProtKB:C0HL13, ECO:0000250|UniProtKB:P98158, ECO:0000269|PubMed:15126248, ECO:0000269|PubMed:23825075}.
• Disease: DISEASE: Donnai-Barrow syndrome (DBS) [MIM:222448]: Rare autosomal recessive disorder characterized by major malformations including agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. The FOAR syndrome was first described as comprising facial anomalies, ocular anomalies, sensorineural hearing loss, and proteinuria. DBS and FOAR were first described as distinct disorders but the classic distinguishing features between the 2 disorders were presence of proteinuria and absence of diaphragmatic hernia and corpus callosum anomalies in FOAR. Early reports noted that the 2 disorders shared many phenotypic features and may be identical. Although there is variability in the expression of some features (e.g., agenesis of the corpus callosum and proteinuria), DBS and FOAR are now considered to represent the same entity. {ECO:0000269|PubMed:17632512}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Thyroid hormone synthesis - Homo sapiens (human);Cholesterol metabolism - Homo sapiens (human);Hedgehog signaling pathway - Homo sapiens (human);HH-Ncore;Vitamin B12 Metabolism;Human Complement System;Hedgehog Signaling Pathway;Signaling by GPCR;Signal Transduction;Metabolism of fat-soluble vitamins;Vesicle-mediated transport;Membrane Trafficking;Metabolism of lipids;Metabolism;Metabolism of steroids;Metabolism of vitamins and cofactors;Clathrin-mediated endocytosis;Vitamin D (calciferol) metabolism;Retinoid metabolism and transport;Cargo recognition for clathrin-mediated endocytosis;G alpha (i) signalling events;Visual phototransduction;GPCR downstream signalling;Signaling events mediated by the Hedgehog family;Steroid hormones (Consensus)

Recessive Scores

• pRec: 0.542

Intolerance Scores

• loftool: 0.00434
• rvis_EVS: 3.32
• rvis_percentile_EVS: 99.42

Haploinsufficiency Scores

• pHI: 0.648
• hipred: Y
• hipred_score: 0.747
• ghis: 0.442

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.949

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Lrp2
• Phenotype: immune system phenotype; renal/urinary system phenotype; skeleton phenotype; digestive/alimentary phenotype; hearing/vestibular/ear 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; vision/eye 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; 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); reproductive system phenotype; pigmentation phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: lrp2a
• Affected structure: posterior segment eye
• Phenotype tag: abnormal
• Phenotype quality: increased depth

Gene ontology

• Biological process: retinoid metabolic process;neural tube closure;secondary heart field specification;outflow tract septum morphogenesis;ventricular compact myocardium morphogenesis;ventricular septum development;lipid metabolic process;endocytosis;receptor-mediated endocytosis;sensory perception of sound;cell population proliferation;male gonad development;metal ion transport;negative regulation of BMP signaling pathway;forebrain development;aorta development;vitamin D metabolic process;lipoprotein transport;positive regulation of neurogenesis;vagina development;coronary artery morphogenesis;membrane organization;pulmonary artery morphogenesis;positive regulation of oligodendrocyte progenitor proliferation;neuron projection arborization;folate import across plasma membrane;positive regulation of lysosomal protein catabolic process
• Cellular component: lysosome;lysosomal membrane;endoplasmic reticulum;Golgi apparatus;plasma membrane;clathrin-coated pit;external side of plasma membrane;integral component of membrane;apical plasma membrane;endocytic vesicle;axon;dendrite;clathrin-coated vesicle membrane;brush border membrane;endosome lumen;receptor complex;extracellular exosome
• Molecular function: low-density lipoprotein particle receptor activity;calcium ion binding;protein binding;drug binding;SH3 domain binding;steroid hormone receptor binding;lipoprotein transporter activity;chaperone binding