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 OMIM: 603506

The LRP5 protein functions as a coreceptor with Frizzled proteins to transduce Wnt signaling, which regulates osteoblast proliferation and differentiation to determine bone mass, and also serves as a coreceptor for norrin signaling required for retinal vascular development. Mutations cause a spectrum of bone disorders including osteoporosis-pseudoglioma syndrome, osteopetrosis, and endosteal hyperostosis, as well as familial exudative vitreoretinopathy and polycystic liver disease. The gene shows high constraint against loss-of-function variants (LOEUF 0.34) and exhibits both autosomal dominant and autosomal recessive inheritance patterns depending on the specific condition.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.346 OMIM phenotypes

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

38 unique Pathogenic / Likely Pathogenic· 224 VUS of 400 total submissions

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GeneReview available — LRP5

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

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

1.67Z-score

OE missense 0.86 (0.81–0.91)

946 obs / 1101.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.22 (0.15–0.34)

0≤0.351.4

Missense OE0.86 (0.81–0.91)

0≤0.61.4

Synonymous OE1.06

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveLRP5-related osteopetrosisGOFAD

definitiveLRP5-related osteoporosis-pseudoglioma syndrome on a spectrum with FEVR with osteopeniaLOFAR

definitiveLRP5-related exudative vitreoretinopathyLOFAD

0.6065th %ile

GOF

0.76top 25%

LOF

0.49top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 55% of P/LP variants are LoF · LOEUF 0.34

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFEleven heterozygous gain-of-function missense mutations within LRP5 are known to prevent the LRP5 inhibitory ligands sclerostin and dickkopf1 from attaching to LRP5's first ÃÂ²-propeller, and thereby explain the rare autosomal dominant (AD) skeletal disorder "high bone mass" (HBM).PMID:31085352

LOFThus, heterozygous loss-of-function mutations in LRP5 can be associated with a bone formation deficit that affects mostly the trabecular compartment and can result in bone fragility during the first years of life.PMID:23886840

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.