Important Variant Information for CYP2D6
Submitted by: Ryan Owen (PharmGKB)
Reviewed by: Under Review
Submitted date: October 5th, 2007
There are Ten Important Variants for CYP2D6.
- CYP2D6: 100C>T
- CYP2D6: 1023 C>T
- CYP2D6: 1659G>A
- CYP2D6: 1707 del T
- CYP2D6: 1846 G>A
- CYP2D6: 2549 del A
- CYP2D6: 2613-2615 del AGA
- CYP2D6: 2850 C>T
- CYP2D6: 2988 G>A
- CYP2D6: 3183 G>A
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Variant Summary: | CYP2D6 100C>T (also seen as 188C>T in the literature) is part of both the non-functional CYP2D6*4 haplotype and the reduced function CYP2D6*10 haplotype. Since CYP2D6 100C>T is present in both a non-functional and a reduced function haplotype, it is not likely to be the causative SNP for the lack of function observed with CYP2D6*4. According to Gaedigk et al [10634130], the presence of CYP2D6 100C>T (188C>T by their nomenclature), and the absence of CYP2D6 1846G>A (1934G>A) is diagnostic of CYP2D6*10. In vitro studies in both COS-1 [2211621]and V79 [12386125] cells have shown that cells transfected with CYP2D6 100C>T alone exhibit reduced function, suggesting that this mutation contributes to the reduced function of the CYP2D6*10 allele. Association studies have examined the role of this variant in contributing to generalized tonic clonic seizures (GTCS) seen in epilepsy (no association found) [16835697] and tardive dyskinesia in Chinese Schizophrenic patients (weakly positive) [16490169]. |
| Key PubMed IDs: | 10634130 2211621 12386125 |
| Genomic Variant & GenBank ID: | C1719T on M33388 |
| mRNA Variant & GenBank ID: | C100T on X08006 |
| Protein Variant & GenBank ID: | P34S on AAH75024 |
| dbSNP rs#: | rs1065852 |
| GoldenPath Position: | chr22:40856638 on hg 18 |
| Key Drugs/Substrates: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Key Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
GM17201 |
| DNA Source Containing Heterozygous Reference Allele(Coriell Lines): |
GM17203 |
| DNA Source Containing Homozygous Minor Allele(Coriell Lines): |
GM17225 |
| Phenotype Data Sets: | Metabolism of yohimbine by human CYP450 isoforms , Lipid measurements in tamoxifen study , Meperidine N-demethylation by human CYP450 isoforms , Thyroid binding globulin in tamoxifen patients , Hot flashes in tamoxifen patients, Lipid measurements in tamoxifen study - set 2 , Pharmacokinetics of Tamoxifen at 4 months |
| Key Haplotypes: | CYP2D6*4, CYP2D6*10 |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Variant Summary: | CYP2D6 1023C>T (also seen as 1111C>T in the literature) was first identified when screening for reduced function alleles in a Zimbabwean population [8971426]. It was identified as being part of the reduced function haplotype CYP2D6*17. According to the genotyping algorithm of Gaedigk et al [1063413], the presence of CYP2D6 1023C>T (1111C>T) and 2850C>T (2938C>T) is diagnostic for CYP2D6*17. A subsequent study examined the role of CYP2D6 1023C>T and two other SNPs found in CYP2D6*17 to see which of the SNPs was causative of the reduced function observed with the haplotype [9415713]. The authors found that the CYP2D6 1023C>T single mutation exhibited normal function in transfected COS-1 cells, but when made in combination with another mutation led to an increased Km (decreased affinity) for bufuralol. Interestingly, when the substrate was codeine, CYP2D6 1023C>T alone was sufficient to cause an increase in the Km of CYP2D6 for codeine, suggesting that this mutation exhibits substrate-specific effects, and may contribute to the reduction in function of CYP2D6*17. |
| Key PubMed IDs: | 8971426 9415713 10634130 |
| Genomic Variant & GenBank ID: | C2642T on M33388 |
| mRNA Variant & GenBank ID: | C320T on X08006 |
| Protein Variant & GenBank ID: | T107I on AAH75024 |
| dbSNP rs#: | rs28371706 |
| GoldenPath Position: | chr22:40855716 on hg 18 |
| Key Drugs/Substrates: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Key Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
GM17242 |
| DNA Source Containing Heterozygous Reference Allele (Coriell Lines): |
GM17155 |
| DNA Source Containing Homozygous Minor Allele(Coriell Lines): |
GM17121 |
| Phenotype Data Sets: | Metabolism of yohimbine by human CYP450 isoforms , Lipid measurements in tamoxifen study , Meperidine N-demethylation by human CYP450 isoforms , Patient responses to tamoxifen, Thyroid binding globulin in tamoxifen patients , Hot flashes in tamoxifen patients , Lipid measurements in tamoxifen study - set 2 , Pharmacokinetics of Tamoxifen at 4 months |
| Key Haplotypes: | CYP2D6*17 |
3. CYP2D6: 1659 G>A
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Variant Summary: | CYP2D6 1659G>A (also seen as 1747G>A in the literature) was first identified by Marez et al [9241659] in a screening of a large European population. Although it is very rare in Europeans, it was later identified as part of the reduced functioning haplotype CYP2D6*29, which is found at an estimated allele frequency of 20% in African Tanzanians [11470994]. Functional characterization of CYP2D6 1659G>A in COS-1 cells showed a slightly reduced activity as measured by bufuralol hydroxylation, but this activity was reduced further when the CYP2D6*29 mutations were made in combination [11470994]. |
| Key PubMed IDs: | 9241659 11470994 |
| Genomic Variant & GenBank ID: | G3278A on M33388 |
| mRNA Variant & GenBank ID: | G408A on X08006 |
| Protein Variant & GenBank ID: | V136I on AAH75024 |
| dbSNP rs#: | N/A |
| GoldenPath Position: | chr22:40855078 on hg 18 |
| Key Drugs/Substrates: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Key Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| Phenotype Data Sets: | None |
| Key Haplotypes: | CYP2D6*29 |
4. CYP2D6: 1707 del T
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Variant Summary: | CYP2D6 2850C>T (also called 2938C>T in the literature) is a common SNP in CYP2D6, and is found in the CYP2D6*2 haplotype among others. CYP2A6*2 activity is slightly reduced [9012401], but is considered to be in the same extensive metabolizer (EM) category as CYP2D6*1 [11972444]. The presence of CYP2D6 2850C>T and the absence of several others is diagnostic of the CYP2D6*2 haplotype according to Gaedigk et al [10634130]. Many Africans or African Americans were misdiagnosed as CYP2D6*2 by this allele, before the discovery of other reduced function haplotypes that share this SNP in common with CYP2D6*2 such as CYP2D6*17 and CYP2D6*29 [11972444]. One study found an association between CYP2D6 2850C>T and generalized tonic clonic seizures (GTCS) among Indians [16835697]. |
| Key PubMed IDs: | 9012401 11972444 10634130 16835697 |
| Genomic Variant & GenBank ID: | C4469T on M33388 |
| mRNA Variant & GenBank ID: | C886T on X08006 |
| Protein Variant & GenBank ID: | R296C on AAH75024 |
| dbSNP rs#: | rs16947 |
| GoldenPath Position: | chr22:40853887 on hg 18 |
| Key Drugs/Substrates: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573] |
| Key Phenotypes/Diseases: | Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
GM17148 |
| DNA Source Containing Heterozygous Reference Allele (Coriell Lines): |
GM17247 |
| DNA Source Containing Homozygous Minor Allele(Coriell Lines): |
GM17232 |
| Phenotype Data Sets: | Metabolism of yohimbine by human CYP450 isoforms , Lipid measurements in tamoxifen study , Meperidine N-demethylation by human CYP450 isoforms , Thyroid binding globulin in tamoxifen patients , Hot flashes in tamoxifen patients , Lipid measurements in tamoxifen study - set 2 , Pharmacokinetics of Tamoxifen at 4 months |
| Key Haplotypes: | CYP2D6*2, CYP2D6*17, CYP2D6*29, CYP2D6*41 |
| Gene HGNC Name: | CYP2D6 |
|---|---|
| Variant Summary: | CYP2D6 2988G>A is an intronic polymorphism that has been shown to be associated with aberrant splicing of CYP2D6 [17112815 17001295]. This splicing defect leads to the omission of exon 6 from some of the transcribed RNA, and leads to a reduction in activity. CYP2D6 2988G>A is diagnostic of the haplotype CYP2D6*41, which is believed to be responsible for the IM phenotype [15289790]. |
| Key PubMed IDs: | 17112815 17001295 15289790 |
| Genomic Variant & GenBank ID: | G4607A on M33388 |
| mRNA Variant & GenBank ID: | A775 del on X08006 |
| Protein Variant & GenBank ID: | splicing defect |
| dbSNP rs#: | rs28371725 |
| GoldenPath Position: | chr22:40853749 on hg 18 |
| Key Drugs/Substrates: | amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [ |