UGT1A1 G71R - GET-Evidence

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Currentness:

UGT1A1 G71R

(UGT1A1 Gly71Arg)


Short summary

This variant, also known as UGT1A1*6, is associated with Gilbert syndrome (found in ~5% of the population) and transient hyperbilirubinemia in infants in east asian populations. This allele appears to have incomplete penetrance and causes reduced enzyme activity.

Variant evidence
Computational 1

Other mutations in this gene associated with disease, NBLOSUM = 4 but polyphen predicts this mutation to be benign.

Functional 1

Enzyme activity of recombinant protein is impaired

See Udomuksorn W et al. 2007 (18004206).

Case/Control 4

OR = 4.6 with significance of p = 9.8 * 10^-5.

See Akaba K et al. 1999 (9929972).

Familial -
 
Clinical importance
Severity 2
Treatability 4
Penetrance 3
 

Impact

Moderate clinical importance, Likely pathogenic

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

Inheritance pattern

other

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr2:234669144: 0.1% (8/10758) in EVS
  • Frequency shown in summary reports: 0.1% (8/10758)

Publications
 

Akaba K, Kimura T, Sasaki A, Tanabe S, Wakabayashi T, Hiroi M, Yasumura S, Maki K, Aikawa S, Hayasaka K. Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese. J Hum Genet. 1999;44(1):22-5. PubMed PMID: 9929972.

The authors report that Gly71Arg is a common mutation involved with hyperbilirubinemia in neonates. Comparing infants that required phototherapy (ie. had severe hyperbilirubinemia) with those that did not produces the following case/control numbers: case (hom): 4, case (het): 8, case(WT): 5, control (hom): 3, control (het): 40, control (WT): 99. Counting alleles, this is: case+: 16, case-: 18, control+: 46, control-: 238. This is an OR = 4.6 with significance of p = 9.8 * 10^-5. Counting homozygotes, case+: 4, case-: 13, control+: 3, control-: 139, producing an OR = 14 and p = 0.0026.

Udomuksorn W, Elliot DJ, Lewis BC, Mackenzie PI, Yoovathaworn K, Miners JO. Influence of mutations associated with Gilbert and Crigler-Najjar type II syndromes on the glucuronidation kinetics of bilirubin and other UDP-glucuronosyltransferase 1A substrates. Pharmacogenet Genomics. 2007 Dec;17(12):1017-29. PubMed PMID: 18004206.

 

Genomes
 

hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
het A @ chr2:234669144

 

huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
het A @ chr2:234669144

 

Other external references
 

    dbSNP
  • rs4148323
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [Gilbert's syndrome]
    [irinotecan]
    *6 is the most common UGT1A1 coding variant found in Asians. It may result in reduced capacity to metabolize irinotecan and hence irinotecan toxicity.
    www.pharmgkb.org/search/annotatedGene/ugt1a1
    Web search results (461 hits -- see all)
  • Gly71Arg Mutation of the Bilirubin UDP ...
    Key Words: Bilirubin uridine diphosphate–glucuronosyltransferase; UGT1A1; G71R; ... We showed a higher frequency of the G71R mutation of the UGT1A1 gene in Japanese ...
    www.med.kobe-u.ac.jp/journal/contents/48/73.pdf
  • UGT1A1 [PharmGKB]
    UGT1A1 is one of 9 isozymes encoded by the UGT1A locus, a superfamily of Phase II drug ... 7 (UGT1A1*28) and a non-synonymous coding variant G71R (UGT1A1*6) ...
    www.pharmgkb.org/views/index.jsp?objId=PA420
  • 1182
    Of the UGT1A isoforms, UGT1A1 is primarily respon- sible for the glucuronidation of ... tabolite of irinotecan (CPT-11), by human UGT1A1 variants, G71R, P229Q, ...
    www.clinchem.org/cgi/reprint/49/7/1182.pdf
  • Contribution of two missense mutations (G71R and Y486D) of ...
    Relative UGT1A1 activity of a single homozygous model of G71R was ... The activity of a single heterozygous model of G71R was somewhat high to develop to the phenotype of ...
    www.ncbi.nlm.nih.gov/pubmed/9630669
  • The University of Chicago Genetic Services Laboratories
    UGT1A1. gene has been identified in the majority of Caucasian individuals with Gilbert ... frequency of the G71R allele is approximately 10% in the general ...
    genes.uchicago.edu/LabPDF/01Gilbert.pdf
  • Prolonged Unconjugated Hyperbilirubinemia Associated With Breast
    gene (UGT1A1) in patients with hereditary unconjugated. hyperbilirubinemia (Crigler-Najjar ... two missense mutations (G71R and Y486D) of the UGT1A1 gene to ...
    pediatrics.aappublications.org/cgi/reprint/106/5/e59.pdf
  • Frequencies of A(TA)7TAA, G71R, and G493R mutations of the ...
    Frequencies of A(TA)7TAA, G71R, and G493R mutations of the UGT1A1 gene in the Malaysian population. ... Mutation screening of both G71R and G493R was performed using ...
    www.ncbi.nlm.nih.gov/pubmed/16210851
  • CiNii - Gly71Arg Mutation of the Bilirubin UDP ...
    ... at codon 71 (G71R), in the coding region of the UGT1A1 gene can cause neonatal ... Therefore, the G71R mutation was present significantly more frequently in the ...
    ci.nii.ac.jp/naid/110000018810
  • UGT1A9 [PharmGKB]
    93 is a common variant of UGT1A1 in Caucasian and African-American populations. ... The *27 variant form of UGT1A1 has very low activity in vitro, so is likely to ...
    www.pharmgkb.org/do/serve?objId=PA419&objCls=Gene

Other in silico analyses
 

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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