LRP5 V667M - GET-Evidence

Curation:
Currentness:

LRP5 V667M

(LRP5 Val667Met)


Short summary

This variant has been implicated in causing osteoporosis-pseudoglioma syndrome in a recessive manner. The gene is strongly implicated in causing the disease, but an insufficient number of controls means this variant’s observation lacks statistical significance. The condition manifests in childhood with early onset osteoporosis and eye problems.

Variant evidence
Computational 2

Gene is associated with the disease, Polyphen2 predicts damaging response

See Gong Y et al. 2001 (11719191).

Functional

No functional data

Case/Control

case/control numbers for this variant lack statistical significance

See Gong Y et al. 2001 (11719191).

Familial

No familial data

 
Clinical importance
Severity 4
Treatability -
Penetrance 5

Published hypothesis is a highly penetrant effect

See Gong Y et al. 2001 (11719191).

 

Impact

High clinical importance, Uncertain pathogenic

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

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr11:68174189: 4.1% (445/10758) in EVS
  • A @ chr11:67930764: 2.3% (3/128) in GET-Evidence
  • Frequency shown in summary reports: 4.1% (445/10758)

Publications
 

Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Jüppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML; Osteoporosis-Pseudoglioma Syndrome Collaborative Group. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001 Nov 16;107(4):513-23. PubMed PMID: 11719191.

This study implicates this gene as causing autosomal recessive osteoporosis-pseudoglioma syndrome. In a study of 28 families this variant was found in one patient — it is unclear whether it was homozygous or heterozygous (presumed compound heterozygous) and was not seen in “>50 control alleles” (which were not matched for ancestry). Assuming control alleles represent 25 individuals, this gives case+: 1, case-: 27, cont+: 0, cont-: 25. These numbers do not have any statistical significance.

Genomes
 

hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het A @ chr11:68174189

 

hu7A4AD1 - CGI sample GS01669-DNA_C05 from PGP sample 42408046
het A @ chr11:68174189

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het A @ chr11:68174189

 

GS19648 - var-GS19648-1100-36-ASM
het A @ chr11:67930765

 

Other external references
 

    dbSNP
  • rs4988321
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the LRP5 gene
    Familial Exudative Vitreoretinopathy
    Familial Exudative Vitreoretinopathy, Autosomal Dominant
    Osteoporosis Pseudoglioma Syndrome
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/LRP5
    PolyPhen-2
  • Score: 0.96 (probably damaging)
    Web search results (54 hits -- see all)
  • Replication of associations between LRP5 and ESRRA variants ...
    LRP5 V667M was genotyped by allele-specific PCR and ESRRA repeats by sizing of PCR products on agarose gels. ... CONCLUSIONS: The association between LRP5 V667M and LS BMD is ...
    www.ncbi.nlm.nih.gov/pubmed/18418639
  • LRP5 - low density lipoprotein receptor-related protein 5
    Thus, it is likely that LRP6 and LRP5 comprise a new class of the LDLR family. ... LRP5 V667M was genotyped by allele-specific PCR and ESRRA repeats by ...
    www.ihop-net.org/UniPub/iHOP/gs/89893.html
  • Anales de Osteología y Osteoporosis
    OSTEOLOGY: -Replication of associations between LRP5 and ESRRA variants and bone ... LRP5 V667M was genotyped by allele-specific PCR and ESRRA repeats by sizing of ...
    analesdemedicina.com/osteologia_osteoporosis/noticia.php?...
  • Association between Bone Mineral Density and LDL Receptor ...
    causing amino acid changes in the LRP5 coding region, and investigated their asso ... LRP5. gene polymorphisms are presented in Table 2. No polymor- phisms of the A400V, V667M, ...
    jkms.kams.or.kr/2004/pdf/06407.pdf
  • The Genetics of Low-Density Lipoprotein Receptor-Related ...
    This signaling cascade is activated by binding of Wnt ligand to the Frizzled/LRP5 receptor complex. ... Q89R, V667M, and A1330V are naturally occurring LRP5 variants found ...
    endo.endojournals.org/cgi/content/full/148/6/2622
  • A haplotype-based analysis of the LRP5 gene in relation to ...
    LRP5 is an important regulator of osteoblast growth and differentiation, affecting bone mass in vertebrates. ... the LRP5 region, including the missense changes p.V667M and p. ...
    www.ncbi.nlm.nih.gov/pubmed/18684085?dopt=Abstract
  • Polymorphisms in the Low-Density Lipoprotein Receptor–Related ...
    To test whether polymorphisms in the LRP5 gene contribute to ... (p.V667M), it is not clear whether and how. it affects the function or expression of the LRP5 protein. ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf
  • Rs4988321 - SNPedia
    LRP5. Chromosome. 11. Orientation. plus. Position. 67930765. Position ... SNP in the LRP5 gene that is also known as Val667Met or V667M; the more common ...
    www.snpedia.com/index.php?title=Rs4988321
  • JKMS vol 19, no. 3
    Association between Bone Mineral Density and LDL Receptor-Related Protein 5 Gene ... amino acid changes in the LRP5 coding region, and investigated their ...
    jkms.kams.or.kr/2004/abstract/407a.html
  • doi:10.1086/368277
    The LDL receptor-related protein 5 (LRP5) gene has been shown ... amino acid change (Q89R, V667M, and A1330V). Two of them (V667M and A1330V) were also ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

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