GGH T151I - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

GGH T151I

(GGH Thr151Ile)


Short summary

 

Variant evidence
Computational -
Functional -
Case/Control -
Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Insufficiently evaluated pharmacogenetic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr8:63938764: 8.3% (889/10758) in EVS
  • A @ chr8:64101317: 14.8% (19/128) in GET-Evidence
  • Frequency shown in summary reports: 8.3% (889/10758)

Publications
 

Cheng Q, Wu B, Kager L, Panetta JC, Zheng J, Pui CH, Relling MV, Evans WE. A substrate specific functional polymorphism of human gamma-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells. Pharmacogenetics. 2004 Aug;14(8):557-67. PubMed PMID: 15284538.

 

van der Straaten RJ, Wessels JA, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Allaart CF, Bogaartz J, Tiller M, Huizinga TW, Guchelaar HJ. Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients. Pharmacogenomics. 2007 Feb;8(2):141-50. PubMed PMID: 17286537.

 

Genomes
 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het A @ chr8:63938764

 

 

 

 

 

 

 

 

 

 

 

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het A @ chr8:63938764

 

GS06985 - var-GS06985-1100-36-ASM
het A @ chr8:64101318

 

GS18526 - var-GS18526-1100-36-ASM
het A @ chr8:64101318

 

GS18558 - var-GS18558-1100-36-ASM
het A @ chr8:64101318

 

GS18940 - var-GS18940-1100-36-ASM
het A @ chr8:64101318

 

GS18956 - var-GS18956-1100-36-ASM
het A @ chr8:64101318

 

GS19239 - var-GS19239-1100-36-ASM
hom A @ chr8:64101318

 

GS19240 - var-GS19240-1100-36-ASM
het A @ chr8:64101318

 

Other external references
 

    dbSNP
  • rs11545078
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [methotrexate]
    GGH 452C>T has been associated with decreased catalytic activity and higher accumulation of long-chain methotrexate-polyglutamate.
    www.ncbi.nlm.nih.gov/pubmed/17286537
  • [Precursor Cell Lymphoblastic Leukemia-Lymphoma]
    [methotrexate]
    Patients (n= 66) with acute lymphoblastic leukemia showed large individual differences in cellular accumulation of long-chain MTXPG after high-dose methotrexate treatment. The frequency of the rs11545078 (452C>T, Thr127Ile) in GGH was significantly different among patients with low (17.6%), intermediate (9.4%) and high (0%) GGH activity (P = 0.025). Caucasians had a significantly higher frequency of the Ile127 allele (10.0%) than African-Americans (4.4%) (P = 0.033). Rs11545078 was detected in 2 of 4 patients with low GGH activity and none of the five patients with high GGH activity. This missense variant significantly increased Km for long chain polyglutamated methotrexate (MTXPG5) (2.7-fold, P = 0.021), and significantly reduced catalytic efficiency (Vmax/Km) for MTXPG5 (by 67.5%, P = 0.003). The structural impact of this missense variant, based on modelling and enzyme kinetic analysis, indicated a significant reduction GGH binding affinity for long chain MTXPG (MTXPG5).
    www.ncbi.nlm.nih.gov/pubmed/15284538
    PolyPhen-2
  • Score: 0.846 (possibly damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 1

Edit history
 

Gene search

"GENE" or "GENE A123C":

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