TABLE 2

CYPD6 rare variants and model results

Variant AllelesGenetic ChangesAmino Acid SubstitutioncDNA Transfection in COS-1 or COS-7cDNA Transfected in HEK293TBaculovirus-Mediated Insect CellsPatient Samples and Clinical Data
CYP2D6*9c.841-843delAAGp.(Lys281del)Dextromethorphan Vmax was significantly reduced from 0.13 pmol/min per pmol of CYP2D6 compared with WT (0.45 pmol/min per pmol CYP2D6). Additionally, dextromethorphan intrinsic clearance was reduced from 0.0081 µL/min per nmol of CYP2D6 to 0.0030 µL/min per nmol of CYP2D6 when CYP2D6*9 was evaluated (Muroi et al., 2014)The Km was increased (20.2 µM vs 15.7 µM), whereas the Vmax (1.06 area ratio/min per pmol CYP2D6 vs 1.39 area ratio/min per pmol) was reduced compared with WT (Saito et al., 2018)N/ALiver samples from 44 White subjects found that a subject with a CYP2D6*9 genotype had 9.2 pmol/mg protein compared with WT 13.0 pmol/mg. Additionally, the Km value of the 1’-hydroxylation was slightly higher, and Vmax was reduced compared with the WT (Shimada et al., 2001)
CYP2D6*10c.100C>T, c.1457G>Cp.(Pro34Ser), p.(Ser486Thr)Decreased enzyme activity following bufuralol and dextromethorphan treatment (Sakuyama et al., 2008)N/AClearance of dextromethorphan O-demethylation and fluoxetine N-demethylation declined by 50-fold and 100-fold (Yu et al., 2002).
CYP2D6*10-mediated bufuralol hydroxylation had an affinity of 12–50 µM and intrinsic clearance value of 0.05–0.24 µL/min per pmol P450. Additionally, the KmCYP2D6*10/KmCYP2D6*1 ratio was 0.5 for (S)-fluoxetine; 1 to 2 for atomoxetine, bufuralol, codeine, debrisoquine, and tramadol; and >3 for dextromethorphan and nortriptyline (Shen et al., 2007)
Mean serum 4-OH-tamoxifen concentrations were 1.3 times lower in Chinese women with breast cancer homozygous for CYP2D6*10 (Xu et al., 2008)
CYP2D6*14Bc.505G>A, c.886C>T, c.1457G>Cp.(Gly169Arg), p.(Arg296Cys), p.(Ser486Thr)Km was reduced from 9.2 µM in WT to 18.9 µM with the CYP2D6*14 variant. Furthermore, the reduced metabolic capacity goes from 0.2 µL/min per pmol to 0.07 µL/min per pmol (Sakuyama et al., 2008)
CYP2D6*14 exhibited <15% n-desmethyltamoxifen 4-hydroxylation, and ∼36% bufuralol 1’-hydroxylation and dextromethorphan O-demethylation compared to WT (Muroi et al., 2014)
N/AN/AA single subject homozygous for *14 was found to be a PM and not an IM, marking the first report of this phenotype (Cai et al., 2007)
CYP2D6*17c.320C>T, c.886C>T, c.1457G>Cp.(Thr107Ile), p.(Arg296Cys), p.(Ser486Thr)CYP2D6*17 exhibited 20% bufuralol hydroxylase activity compared with WT (Oscarson et al., 1997)
N-desmethyltamoxifen showed 10% hydroxylation activity of WT (Muroi et al., 2014)
N/AThe reaction rate for DXM metabolism of the DXM O-demethylation and N-demethylation decreased 10-fold, and the estimated intrinsic clearance of these metabolites was decreased 6% and 33% (Yu et al., 2002).
The estimated intrinsic clearance for fluoxetine N-demethylated metabolite, norfluoxetine, decreased approximately four-fold and another two-fold with the c.320C>T p.(Thr107Ile) substitution (Yu et al., 2002). The c.320C>T p.(Thr107Ile) substitution led to a six-fold decrease in codeine metabolism
10-fold higher parent-to-metabolite ratios of debrisoquine and dextromethorphan in homozygous Tanzanians (Wennerholm et al., 2002)
CYP2D6*29c.406G>A+c.408G>C, c.886C>T, c.1012G>A, c.1457G>Cp.(Val136Met), p.(Arg296Cys), p.(Val338Met), p.(Ser486Thr)The catalytic activity of hydroxylation of bufuralol and debrisoquine was reduced to 23% and 63% compared with WT (Wennerholm et al., 2001).
The estimated intrinsic clearance of dextromethorphan in COS-7 cells was 47%, Vmax was reduced (40%), and a higher affinity was observed compared with CYP2D6*2. Additionally, the estimated intrinsic clearance of bufuralol is 64%, reduced Vmax (36%), and reduced affinity compared with CYP2D6*2 (Gaedigk et al., 2002).
N/AN/ATanzanian subjects homozygous for CYP2D6*29 displayed higher metabolic ratios for dextromethorphan and metoprolol (Wennerholm et al., 2002).
The single patient with CYP2D6*29 genotype demonstrated reduced clearance (4.67 mL/min) compared with WT (5.7 mL/min) (Grimsrud et al., 2019)
CYP2D6*49c.100C>T, c.358G>A, c.1457G>Cp.(Pro34Ser), p.(Phe120Ile), p.(Ser486Thr)O-demethylation was significantly increased to 323 µM compared with WT (10 µM) (Matsunaga et al., 2009)
  • DXM, dextromethorphan.

  • *Italicized genetic changes (nomenclature NM_000106.6 at the ATG start site) and amino acid substitutions, if applicable, are specific to the variant alleles and used for classification.