LRP6

LDL receptor related protein 6, the group of Low density lipoprotein receptors

Basic information

Region (hg38): 12:12116024-12267044

Links

ENSG00000070018 ∙ NCBI:4040 ∙ OMIM:603507 ∙ HGNC:6698 ∙ Uniprot:O75581 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• tooth agenesis (Supportive), mode of inheritance: AD
• tooth agenesis (Definitive), mode of inheritance: AD
• coronary artery disease, autosomal dominant 2 (Limited), mode of inheritance: Unknown
• tooth agenesis, selective, 7 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Coronary artery disease, autosomal dominant 2	AD	Cardiovascular	Preventive measures related to control of contributing factors associated with coronary artery disease may be beneficial to reduce morbidity and mortality	Cardiovascular; Dental	17332414; 23703864; 26387593
While severe manifestations may occur later in life, surveillance and preventive measures may be beneficial prior to adulthood

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LRP6 gene.

• not provided (304 variants)
• Inborn genetic diseases (42 variants)
• Tooth agenesis, selective, 7 (13 variants)
• Tooth agenesis (6 variants)
• Orofacial cleft (5 variants)
• Autosomal dominant polycystic liver disease (4 variants)
• Tooth agenesis, selective, 7;Coronary artery disease, autosomal dominant 2 (3 variants)
• Coronary artery disease, autosomal dominant 2 (3 variants)
• Orofacial cleft;Tooth agenesis (3 variants)
• not specified (2 variants)
• LRP6-related condition (2 variants)
• Autosomal dominant polycystic kidney disease (2 variants)
• Oligodontia (2 variants)
• Coronary artery disorder (1 variants)
• Generalized hypopigmentation;Microcephaly;Sparse scalp hair;High myopia;Short stature (1 variants)
• Coronary artery disease, autosomal dominant 2;Tooth agenesis, selective, 7 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LRP6 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				33	21	54
missense	1	3	150	7	10	171
nonsense	10	3				13
start loss			1			1
frameshift	12	2	3			17
inframe indel						0
splice donor/acceptor (+/-2bp)	5	3				8
splice region			4	7	5	16
non coding				13	64	77
Total	28	11	154	53	95

Highest pathogenic variant AF is 0.0000197

Variants in LRP6

This is a list of pathogenic ClinVar variants found in the LRP6 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-12121145-G-A			Uncertain significance (Oct 23, 2023)
12-12121146-G-A		Keratoconus	Uncertain significance (Feb 18, 2018)
12-12121168-G-A			Likely benign (Jul 13, 2023)
12-12121185-T-C			Uncertain significance (Apr 11, 2022)
12-12121249-G-A			Benign (Dec 31, 2023)
12-12121270-AG-A			Likely pathogenic (May 01, 2021)
12-12121319-A-G			Uncertain significance (Mar 01, 2024)
12-12121341-G-A			Uncertain significance (May 26, 2022)
12-12121367-G-C			Uncertain significance (Jan 31, 2024)
12-12121368-T-G			Uncertain significance (Dec 13, 2023)
12-12121374-AG-A		Orofacial cleft;Tooth agenesis	Pathogenic (Mar 10, 2016)
12-12121384-G-T			Benign/Likely benign (Dec 18, 2023)
12-12121389-G-T			Uncertain significance (May 27, 2022)
12-12121400-C-T			Uncertain significance (Oct 17, 2023)
12-12121401-G-A		Inborn genetic diseases	Uncertain significance (Mar 02, 2023)
12-12121417-G-A			Likely benign (Oct 06, 2021)
12-12121426-A-T			Likely benign (Mar 25, 2022)
12-12124372-C-CA			Benign (Jun 19, 2021)
12-12124545-T-G			Likely benign (Mar 23, 2021)
12-12124587-G-A		Inborn genetic diseases	Conflicting classifications of pathogenicity (Apr 15, 2023)
12-12124601-T-C			Uncertain significance (Feb 19, 2022)
12-12124626-A-G		Inborn genetic diseases	Uncertain significance (Jan 05, 2022)
12-12124628-C-T		Inborn genetic diseases	Uncertain significance (Jun 17, 2022)
12-12124642-G-C			Likely benign (Dec 18, 2021)
12-12124651-AG-A			Uncertain significance (Oct 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LRP6	protein_coding	protein_coding	ENST00000261349	23	150988

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.697	0.303	125725	0	23	125748	0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.75	657	888	0.740	0.0000493	10592
Missense in Polyphen		216	366.82	0.58885		4221
Synonymous	-0.919	325	305	1.07	0.0000153	3113
Loss of Function	6.79	19	87.6	0.217	0.00000616	926

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000334	0.000333
Ashkenazi Jewish	0.00	0.00
East Asian	0.000164	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.0000704	0.0000703
Middle Eastern	0.000164	0.000163
South Asian	0.000131	0.000131
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor- ligand complexes into ribosome-sized signalsomes. Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in bone formation. The Wnt-induced Fzd/LRP6 coreceptor complex recruits DVL1 polymers to the plasma membrane which, in turn, recruits the AXIN1/GSK3B-complex to the cell surface promoting the formation of signalsomes and inhibiting AXIN1/GSK3- mediated phosphorylation and destruction of beta-catenin. Required for posterior patterning of the epiblast during gastrulation (By similarity). {ECO:0000250, ECO:0000269|PubMed:11357136, ECO:0000269|PubMed:11448771, ECO:0000269|PubMed:15778503, ECO:0000269|PubMed:16341017, ECO:0000269|PubMed:16513652, ECO:0000269|PubMed:17326769, ECO:0000269|PubMed:17400545, ECO:0000269|PubMed:19107203, ECO:0000269|PubMed:19293931, ECO:0000269|PubMed:19801552}.
• Disease: DISEASE: Coronary artery disease, autosomal dominant, 2 (ADCAD2) [MIM:610947]: A common heart disease characterized by reduced or absent blood flow in one or more of the arteries that encircle and supply the heart. Its most important complication is acute myocardial infarction. {ECO:0000269|PubMed:17332414, ECO:0000269|PubMed:23703864}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tooth agenesis, selective, 7 (STHAG7) [MIM:616724]: An autosomal dominant form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). {ECO:0000269|PubMed:26387593}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• 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);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;wnt signaling pathway;segmentation clock;multi-step regulation of transcription by pitx2;wnt lrp6 signalling;inactivation of gsk3 by akt causes accumulation of b-catenin in alveolar macrophages;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;Degradation of beta catenin;TCF dependent signaling in response to WNT;Canonical Wnt signaling pathway;Wnt Mammals;Presenilin action in Notch and Wnt signaling (Consensus)

Recessive Scores

• pRec: 0.472

Intolerance Scores

• loftool: 0.0402
• rvis_EVS: -1.7
• rvis_percentile_EVS: 2.57

Haploinsufficiency Scores

• pHI: 0.472
• hipred: Y
• hipred_score: 0.698
• ghis: 0.616

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.986

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Lrp6
• Phenotype: adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region 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); craniofacial phenotype; immune system phenotype; homeostasis/metabolism phenotype; cellular phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; embryo 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; reproductive system phenotype; vision/eye 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; skeleton phenotype; renal/urinary system phenotype

Zebrafish Information Network

• Gene name: lrp6
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: wholly ventralized

Gene ontology

• Biological process: gastrulation with mouth forming second;neural tube closure;negative regulation of protein phosphorylation;pericardium morphogenesis;negative regulation of protein kinase activity;positive regulation of cytosolic calcium ion concentration;chemical synaptic transmission;embryonic pattern specification;anterior/posterior pattern specification;neural crest formation;neural crest cell differentiation;Wnt signaling pathway;cerebellum morphogenesis;thalamus development;cerebral cortex development;embryonic limb morphogenesis;midbrain development;midbrain-hindbrain boundary development;negative regulation of smooth muscle cell apoptotic process;external genitalia morphogenesis;odontogenesis of dentin-containing tooth;response to peptide hormone;canonical Wnt signaling pathway involved in neural crest cell differentiation;canonical Wnt signaling pathway involved in regulation of cell proliferation;positive regulation of cell cycle;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;bone remodeling;embryonic camera-type eye morphogenesis;positive regulation of DNA-binding transcription factor activity;roof of mouth development;convergent extension;embryonic retina morphogenesis in camera-type eye;canonical Wnt signaling pathway;face morphogenesis;bone morphogenesis;branching involved in mammary gland duct morphogenesis;trachea cartilage morphogenesis;cellular response to cholesterol;dopaminergic neuron differentiation;negative regulation of protein serine/threonine kinase activity;protein localization to plasma membrane;primitive streak formation;negative regulation of canonical Wnt signaling pathway;receptor-mediated endocytosis involved in cholesterol transport;Wnt signaling pathway involved in somitogenesis;axis elongation involved in somitogenesis;cell-cell adhesion;toxin transport;beta-catenin destruction complex disassembly;midbrain dopaminergic neuron differentiation;Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation
• Cellular component: extracellular region;early endosome;endoplasmic reticulum;Golgi apparatus;plasma membrane;caveola;cell surface;integral component of membrane;cytoplasmic vesicle;early endosome membrane;neuronal cell body;synapse;Wnt-Frizzled-LRP5/6 complex;Wnt signalosome
• Molecular function: low-density lipoprotein particle receptor activity;signaling receptor binding;frizzled binding;protein binding;Wnt-protein binding;kinase inhibitor activity;toxin transmembrane transporter activity;apolipoprotein binding;identical protein binding;protein homodimerization activity;Wnt-activated receptor activity;coreceptor activity involved in Wnt signaling pathway;coreceptor activity involved in canonical Wnt signaling pathway