CYP2D6 P34S - GET-Evidence

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

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Curation:
Currentness:

CYP2D6 P34S

(CYP2D6 Pro34Ser)


Short summary

This variant is associated with poor metabolism of debrisoquine. The variant is also known as CYP2D6*10 or CYP2D6 (J) or CYP2D6 (Ch1, Ch2). Zateyshchikov et al. report that heterozygotes carrying this variant are more sensitive to betaxolol therapy.

Variant evidence
Computational 2

Other mutations in this gene are associated with the phenotype. NBLOSUM = 2.

See Kagimoto M et al. 1990 (2211621), unpublished research (below).

Functional 2

Chimeric constructs expressing this variant have abolished activity. Liver cells have reduced activity depending to the number of copies of this variant.

See Kagimoto M et al. 1990 (2211621), Nakamura K et al. 2002 (12051754), unpublished research (below).

Case/Control 3

Although OR data doesn’t exist for this, the magnitude and significance of Zateyshchikov et al. seems to put this at three stars.

See Zateyshchikov DA et al. 2007 (17635183), unpublished research (below).

Familial

See unpublished research (below).

 
Clinical importance
Severity 2

Poor metabolizer phenotype causes individuals to be more sensitive to some drugs, which can make them more effective or can cause adverse effects.

See Zateyshchikov DA et al. 2007 (17635183), unpublished research (below).

Treatability 2

Anecdotal & developing evidence that some drugs are more effective, or should be lower, for low metabolizers.

See Lee SY et al. 2004 (15483356), de Leon J et al. 2005 (15669884), unpublished research (below).

Penetrance -
 

Impact

Insufficiently evaluated pharmacogenetic

(The "insufficiently evaluated" 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 @ chr22:42526694: 18.7% (2012/10742) in EVS
  • A @ chr22:40856637: 22.4% (26/116) in GET-Evidence
  • Frequency shown in summary reports: 18.7% (2012/10742)

Publications
 

Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem. 1990 Oct 5;265(28):17209-14. PubMed PMID: 2211621.

This variant was found alongside several others (Leu91Met, His94Arg, and Ser486Thr) as well as a nucleotide change that may disrupt splicing. Chimeric constructs were created to test each variant; the Pro34Ser appeared to have the strongest effect, abolishing the activity of the expressed protein.

Nakamura K, Ariyoshi N, Yokoi T, Ohgiya S, Chida M, Nagashima K, Inoue K, Kodama T, Shimada N, Kamataki T. CYP2D6.10 present in human liver microsomes shows low catalytic activity and thermal stability. Biochem Biophys Res Commun. 2002 May 10;293(3):969-73. PubMed PMID: 12051754.

 

Lee SY, Ki CS, Hong KS, Kim JW. A case report of a poor metabolizer of CYP2D6 presented with unusual responses to nortriptyline medication. J Korean Med Sci. 2004 Oct;19(5):750-2. PubMed PMID: 15483356; PubMed Central PMCID: PMC2816343.

 

de Leon J, Susce MT, Pan RM, Fairchild M, Koch WH, Wedlund PJ. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005 Jan;66(1):15-27. PubMed PMID: 15669884.

 

Zateyshchikov DA, Minushkina LO, Brovkin AN, Savel'eva EG, Zateyshchikova AA, Manchaeva BB, Nikitin AG, Sidorenko BA, Nosikov VV. Association of CYP2D6 and ADRB1 genes with hypotensive and antichronotropic action of betaxolol in patients with arterial hypertension. Fundam Clin Pharmacol. 2007 Aug;21(4):437-43. PubMed PMID: 17635183.

Investigating sensitivity to betaxolol therapy, the authors found that carriers of this variant are more sensitive. Compared against subjects homozygous for Pro34, heterozygotes had a larger changes in response to medication in resting heart rate (1.8x, p = 0.023), exercising diastolic blood pressure (1.5x, p = 0.022), exercising heart rate (1.25x, p = 0.043), and exercise duration (7.6x, p = 0.045). Decline of mean daytime systolic blood pressure was 4x, significance = 0.001.

Genomes
 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
hom A @ chr22:42526694

 

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het A @ chr22:42526694

 

 

hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
hom A @ chr22:42526694

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het A @ chr22:42526694

 

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
hom A @ chr22:42526694

 

hu92FD55 - CGI sample GS01669-DNA_A04 from PGP sample 08188426
hom A @ chr22:42526694

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het A @ chr22:42526694

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
het A @ chr22:42526694

 

huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
hom A @ chr22:42526694

 

huFFAD87 - CGI sample GS01669-DNA_H05 from PGP sample 10971581
het A @ chr22:42526694

 

GS10851 - var-GS10851-1100-36-ASM
het A @ chr22:40856638

 

GS18526 - var-GS18526-1100-36-ASM
het A @ chr22:40856638

 

GS18537 - var-GS18537-1100-36-ASM
het A @ chr22:40856638

 

GS18555 - var-GS18555-1100-36-ASM
hom A @ chr22:40856638

 

GS18558 - var-GS18558-1100-36-ASM
het A @ chr22:40856638

 

GS18940 - var-GS18940-1100-36-ASM
het A @ chr22:40856638

 

GS18947 - var-GS18947-1100-36-ASM
het A @ chr22:40856638

 

GS18956 - var-GS18956-1100-36-ASM
het A @ chr22:40856638

 

GS19649 - var-GS19649-1100-36-ASM
het A @ chr22:40856638

 

GS19669 - var-GS19669-1100-36-ASM
het A @ chr22:40856638

 

GS19700 - var-GS19700-1100-36-ASM
het A @ chr22:40856638

 

GS19735 - var-GS19735-1100-36-ASM
het A @ chr22:40856638

 

GS20509 - var-GS20509-1100-36-ASM
het A @ chr22:40856638

 

Other external references
 

    dbSNP
  • rs1065852
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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