LRP5 A1330V - GET-Evidence


LRP5 A1330V

(LRP5 Ala1330Val)

Short summary

In a study of a UK population this variant was associated with a small increased risk of osteoporosis and osteoporotic bone fractures, with each copy of the variant presumed to have an additive effect. A study in Chinese young men failed to find an association with peak bone density.

Variant evidence
Computational 1

Gene is associated with a disease that causes early-onset osteoporosis
PolyPhen: Benign score 0.000
SIFT: Tolerated 0.63
GVGD: GV 0.00; GD 65.28; Class 65
Variant Effect Predictor (Ensembl ):
Mutation Tasting Prediction: Polymorphism, P value: 0. 538979; protein features (might be) affected (Detail: aa 32-1384 TOPO_DOM Extracellular (potential) gets lost; aa 1297-1333 DOMAIN LDL-receptor class A2 gets lost)

Functional -
Case/Control 3

p = 0.02 for increased risk of osteoporotic fracture

See Richards JB et al. 2008 (18455228).


No familial data

Clinical importance
Severity 2

Osteoporosis is late-onset and may not be sympomatic

Treatability 4

Lifestyle changes can reduce risk of osteoporosis

Penetrance 2

Small increased risk of osteoporotic bone fracture

See Richards JB et al. 2008 (18455228), unpublished research (below).



Low clinical importance, Uncertain pathogenic

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

We estimate the increased risk of bone fracture using Richards et al.‘s data. Starting with the reported odds ratio for this variant associated with osteoporotic fracture of 1.3, if the control allele frequency was 0.12 then the allele frequency in cases would have been 0.151. If the average risk of fracture is 5%, then this would be associated with an attributable increased risk of 1.2%.

Allele frequency

  • T @ chr11:68201295: 11.0% (1186/10746) in EVS
  • T @ chr11:67957870: 16.4% (21/128) in GET-Evidence
  • Frequency shown in summary reports: 11.0% (1186/10746)


Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, Andrew T, Falchi M, Gwilliam R, Ahmadi KR, Valdes AM, Arp P, Whittaker P, Verlaan DJ, Jhamai M, Kumanduri V, Moorhouse M, van Meurs JB, Hofman A, Pols HA, Hart D, Zhai G, Kato BS, Mullin BH, Zhang F, Deloukas P, Uitterlinden AG, Spector TD. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet. 2008 May 3;371(9623):1505-12. PubMed PMID: 18455228; PubMed Central PMCID: PMC2679414.

This genome-wide association study investigating the influence of common variants on osteoporosis found an association of this variant with decreased bone mineral density. Replicates investigating 99 high-significance SNPs (39 lumbar, 60 femoral) found a p-value of 1.2*10^-6 for this variant. Each allele was associated with a -0.12 standard deviation in lumbar spine bone density.

The rs3736228 was also associated with an increased risk of osteoporotic fracture, with a combined odds ratio of 1.3, p = 0.02.

Kruk M, Ralston SH, Albagha OM. LRP5 Polymorphisms and response to risedronate treatment in osteoporotic men. Calcif Tissue Int. 2009 Mar;84(3):171-9. Epub 2009 Jan 16. PubMed PMID: 19148563.


Yu JB, Ke YH, He JW, Zhang H, Hu WW, Hu YQ, Li M, Liu YJ, Gu JM, Fu WZ, Gao G, Yue H, Xiao WJ, Zhang ZL. No association between LRP5 gene polymorphisms and bone and obesity phenotypes in Chinese male-offspring nuclear families. Acta Pharmacol Sin. 2010 Nov;31(11):1464-9. Epub 2010 Oct 18. PubMed PMID: 20953208.

1244 young Chinese men from 411 Chinese nuclear families were PCR-genotyped at the Q89R, N740N, and A1330 sites in the gene. This was done to test the effect of Lipoprotein Receptor-related Protein 5 mutations on obesity and bone density in young Chinese men. The results of this investigation suggest that common polymorphisms of the LRP5 gene do not significantly influence bone mass and/or obesity.


hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
het T @ chr11:68201295


hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het T @ chr11:68201295



hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
hom T @ chr11:68201295



hu7A4AD1 - CGI sample GS01669-DNA_C05 from PGP sample 42408046
het T @ chr11:68201295


hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het T @ chr11:68201295


hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het T @ chr11:68201295


huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het T @ chr11:68201295


huD81F3D - CGI sample GS01173-DNA_D06 from PGP sample 69488604
het T @ chr11:68201295


GS07357 - var-GS07357-1100-36-ASM
het T @ chr11:67957871


GS10851 - var-GS10851-1100-36-ASM
het T @ chr11:67957871


GS18526 - var-GS18526-1100-36-ASM
het T @ chr11:67957871


GS18537 - var-GS18537-1100-36-ASM
het T @ chr11:67957871


GS18555 - var-GS18555-1100-36-ASM
het T @ chr11:67957871


GS18558 - var-GS18558-1100-36-ASM
het T @ chr11:67957871


GS18940 - var-GS18940-1100-36-ASM
het T @ chr11:67957871


GS18947 - var-GS18947-1100-36-ASM
het T @ chr11:67957871


GS18956 - var-GS18956-1100-36-ASM
het T @ chr11:67957871


GS19025 - var-GS19025-1100-36-ASM
het T @ chr11:67957871


GS19648 - var-GS19648-1100-36-ASM
het T @ chr11:67957871


GS19649 - var-GS19649-1100-36-ASM
het T @ chr11:67957871


GS19735 - var-GS19735-1100-36-ASM
het T @ chr11:67957871


GS20509 - var-GS20509-1100-36-ASM
het T @ chr11:67957871


Other external references

  • rs3736228
  • GeneTests records for the LRP5 gene
    Familial Exudative Vitreoretinopathy
    Familial Exudative Vitreoretinopathy, Autosomal Dominant
    Osteoporosis Pseudoglioma Syndrome
  • Bone mineral density (rs3736228-T)
    Richards 29-Apr-08 in Lancet
    OR or beta: 0.13 [NR] SD decrease
    Risk allele frequency: 0.14
    p-value: 6.00E-12
    Initial sample: 2,094 women
    Replication sample: 6,463 individuals
  • [Bone Diseases, Metabolic; Bone Resorption; Fractures, Bone; Hip Fractures; Osteoporosis]
    This variant is associated with decreased bone mineral density and an increased risk of both osteoporotic fractures and osteoporosis.
  • [Bone Diseases; Bone Diseases, Metabolic; Fractures, Bone]
    GWAS Results: Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study (Initial Sample Size: 2,094 women; Replication Sample Size: 6,463 individuals; Risk Allele: rs3736228-T). This variant is associated with Bone mineral density.; Web Resource:
  • [Osteoporosis]
    This variant was associated with hip bone mineral density (BMD) in osteoporotic men, but did not appear to be associated with response to risedronate treatment.
  • Score: 0 (benign)

Other in silico analyses

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 4

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Gene search

"GENE" or "GENE A123C":

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