LRP5

Chr 11ADAR

LDL receptor related protein 5

Also known as: BMND1, EVR1, EVR4, HBM, LR3, LRP-5, LRP-7, LRP7

NCBI Gene: 4041 ENSG00000162337 UniProt: O75197

This gene encodes a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins and was originally cloned on the basis of its association with type 1 diabetes mellitus in humans. This protein plays a key role in skeletal homeostasis and many bone density related diseases are caused by mutations in this gene. Mutations in this gene also cause familial exudative vitreoretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

Primary Disease Associations & Inheritance

[Bone mineral density variability 1, high bone mass]MIM #601884

Endosteal hyperostosisMIM #144750

Exudative vitreoretinopathy 4MIM #601813

ADAR

Osteopetrosis, autosomal dominant 1MIM #607634

Osteoporosis-pseudoglioma syndromeMIM #259770

Polycystic liver disease 4 with or without kidney cystsMIM #617875

UniProtVitreoretinopathy, exudative 1

UniProtVitreoretinopathy, exudative 4

UniProtHigh bone mass trait

UniProtVan Buchem disease 2

500

ClinVar variants

Pathogenic / LP

0.51

pLI score

Active trials

Clinical Summary— LRP5

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Gene-Disease Validity (ClinGen)

LRP5-related exudative vitreoretinopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.51) — some intolerance to loss-of-function variants.

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ClinVar Variants

59 Pathogenic / Likely Pathogenic· 291 VUS of 500 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.34LOEUF

pLI 0.510

Z-score 5.94

OE 0.22 (0.15–0.34)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.67Z-score

OE missense 0.86 (0.81–0.91)

946 obs / 1101.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.22 (0.15–0.34)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.81–0.91)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06

0≤1.21.6

LoF obs/exp: 15 / 67.8Missense obs/exp: 946 / 1101.8Syn Z: -1.15

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37

Likely Pathogenic22

VUS291

Likely Benign143

Benign1

Conflicting6

Pathogenic

Likely Pathogenic

291

VUS

143

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	21	3	13	0	37
Likely Pathogenic	8	11	3	0	22
VUS	3	262	23	3	291
Likely Benign	0	2	57	84	143
Benign	0	0	1	0	1
Conflicting	—				6
Total	32	278	97	87	500

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

LRP5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

LRP5-related osteopetrosis

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkeletal

G2P ↗

missense variantinframe deletioninframe insertion

LRP5-related osteoporosis-pseudoglioma syndrome on a spectrum with FEVR with osteopenia

definitive

ARLoss Of FunctionAbsent Gene Product

Dev. DisordersEyeSkeletal

G2P ↗

LRP5-related exudative vitreoretinopathy

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. DisordersEye

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 5; LRP5

MIM #603506 · *

[Bone mineral density variability 1, high bone mass]

MIM #601884