LRP6

protein-coding

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

Gene summary

This gene encodes a member of the low density lipoprotein (LDL) receptor gene family. LDL receptors are transmembrane cell surface proteins involved in receptor-mediated endocytosis of lipoprotein and protein ligands. The protein encoded by this gene functions as a receptor or, with Frizzled, a co-receptor for Wnt and thereby transmits the canonical Wnt/beta-catenin signaling cascade. Through its interaction with the Wnt/beta-catenin signaling cascade this gene plays a role in the regulation of cell differentiation, proliferation, and migration and the development of many cancer types. This protein undergoes gamma-secretase dependent RIP- (regulated intramembrane proteolysis) processing but the precise locations of the cleavage sites have not been determined.[provided by RefSeq, Dec 2009]

MANE transcript

NM_002336.3

Inheritance

ClinVar variants

P:85U:427B:172

Top phenotype

Coronary artery disease, autosomal dominant 2

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr12:12,116,025-12,267,044

External References & Databases

Ensembl (ENSG00000070018)

Transcript & Mutation Effects

hg38 • Region Span ~151.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

tooth agenesis, selective, 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014749

Submitter: Labcorp Genetics (formerly Invitae)

tooth agenesis, selective, 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014749

Submitter: G2P

tooth agenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005486

Submitter: Orphanet

tooth agenesisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005486

Submitter: Illumina

tooth agenesis, selective, 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014749

Submitter: PanelApp Australia

coronary artery disease, autosomal dominant 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012586

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Coronary artery disease, autosomal dominant 2AD

Manifestation: Cardiovascular; Dental

Intervention: Cardiovascular

Rationale: Preventive measures related to control of contributing factors associated with coronary artery disease may be beneficial to reduce morbidity and mortality

Comments: While severe manifestations may occur later in life, surveillance and preventive measures may be beneficial prior to adulthood

Refs: 17332414; 23703864; 26387593

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LRP6 variants in ClinVar

24 Conditions Cataloged

not providedTotal: 560

Inborn genetic diseasesTotal: 189

Tooth agenesis, selective, 7Total: 41

not specifiedTotal: 30

LRP6-related disorderTotal: 29

Coronary artery disease, autosomal dominant 2Total: 21

Autosomal dominant polycystic liver diseaseTotal: 10

Tooth agenesisTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002336.3. 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			7 clinvar	125 clinvar	17 clinvar	149
missense	4 clinvar	8 clinvar	409 clinvar	23 clinvar	7 clinvar	451
nonsense	21 clinvar	8 clinvar	2 clinvar			31
start loss			1 clinvar			1
frameshift	24 clinvar	8 clinvar	2 clinvar			34
splice donor/acceptor (+/-2bp)	6 clinvar	6 clinvar	6 clinvar			18
Total	55	30	427	148	24	684

Highest pathogenic variant AF is 0.00002120563

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002336.3	RefSeq	NP_002327.2	23	MANE Select
ENST00000261349.9	Ensembl	ENSP00000261349.4	23	MANE Select
NM_001414244.1	RefSeq	NP_001401173.1	24	Standard
NM_001414245.1	RefSeq	NP_001401174.1	23	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lrp6	Danio rerio	Structure: whole organism Quality: wholly ventralized abnormal

Gene / Model

Organism

Observed Phenotype

lrp6

Danio rerio

Structure: whole organism

Quality: wholly ventralized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

gastrulation with mouth forming second
neural tube closure
negative regulation of protein phosphorylation
pericardium morphogenesis
negative regulation of protein kinase activity

Molecular Function

low-density lipoprotein particle receptor activity
signaling receptor binding
frizzled binding
protein binding
Wnt-protein binding

Cellular Component

extracellular region
early endosome
endoplasmic reticulum
Golgi apparatus
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261349
Coding exons: 23
Length: 150988
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125748
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.75	657	888	0.740	0.0000493	10592
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.472

Intolerance Scores

LoFtool: 0.0402
RVIS EVS: -1.7
RVIS percentile EVS: 2.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.986

Gene Damage Prediction

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