A novel intronic mutation, 2988G>A, with high predictivity for impaired function of cytochrome P450 2D6 in white subjects

Clin Pharmacol Ther. 2004 Aug;76(2):128-38. doi: 10.1016/j.clpt.2004.04.009.


Background: Individuals with the cytochrome P450 (CYP) 2D6 intermediate metabolizer (IM) phenotype have low residual enzyme activity and compose about 10% to 15% of white populations. Their identification is clinically relevant but remains unsatisfactory because of incomplete characterization of the major allele involved, termed CYP2D6*41 (-1584C, R296C, S486T).

Methods: To search for novel mutations, resequencing of the entire CYP2D6 gene was performed in selected individuals. Genotype-phenotype correlation analysis was done in a population sample of 308 white subjects phenotyped with sparteine and previously genotyped for all major alleles.

Results: A total of 16 novel polymorphic positions were identified, of which 7 were located within 2.4 kilobases of previously uncharacterized 2D7-2D6 intergenic sequence and 9 were located within intronic regions. The novel mutation 2988G>A in intron 6 appeared to be specifically associated with the IM phenotype. Further analysis in the population sample demonstrated that 2988G>A was strongly linked to allele *41 but not to any other alleles including *1, *2, *2xN, *4, *6, *7, *8, *9, *10, and *35. The overall frequency of the novel polymorphism was 8.4% in the normal white population. Compared with conventionally determined *41, 2988G>A was shown to have improved predictivity for the IM phenotype. With 2988G>A being taken into account, alleles *1, *2, and *35 (-1584G, V11M, R296C, S486T) were found to be phenotypically equivalent.

Conclusions: CYP2D6 genotyping can be considerably simplified by using 2988G>A as a marker for *41 and by omitting genotyping for the functionally equivalent alleles *2 and *35.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Analysis of Variance
  • Base Sequence
  • Cohort Studies
  • Cytochrome P-450 CYP2D6 / genetics*
  • DNA Primers / analysis
  • Female
  • Genetic Testing
  • Genetic Variation
  • Genetics, Population
  • Genotype
  • Germany
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Polymerase Chain Reaction
  • Polymorphism, Restriction Fragment Length
  • Probability
  • Sensitivity and Specificity
  • Statistics, Nonparametric
  • White People / genetics*


  • DNA Primers
  • Cytochrome P-450 CYP2D6