This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Likely benign; drug response; other
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 6
- First in ClinVar:
- Apr 4, 2013
- Most recent Submission:
- May 19, 2020
- Last evaluated:
- May 1, 2019
- Accession:
- VCV000016893.7
- Variation ID:
- 16893
- Description:
- single nucleotide variant
Help
CYP2D6*10
- Allele ID
- 31932
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 22q13.2
- Genomic location
- 22: 42130692 (GRCh38) GRCh38 UCSC
- 22: 42526694 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000106.6:c.100C>T MANE Select NP_000097.3:p.Pro34Ser missense NM_001025161.3:c.100C>T NP_001020332.2:p.Pro34Ser missense NC_000022.11:g.42130692G>A NC_000022.10:g.42526694G>A NG_008376.3:g.4300C>T NG_008376.4:g.5119C>T LRG_303:g.5119C>T LRG_303t1:c.100C>T LRG_303p1:p.Pro34Ser P10635:p.Pro34Ser - Protein change
- P34S
- Other names
- NM_000106.6(CYP2D6):c.100C>T (p.Pro34Ser)
- Canonical SPDI
- NC_000022.11:42130691:G:A
- Functional consequence
- Decreased function
- Global minor allele frequency (GMAF)
- 0.23802 (A)
- Allele frequency
- Trans-Omics for Precision Medicine (TOPMed) 0.19196
- 1000 Genomes Project 0.23802
- The Genome Aggregation Database (gnomAD), exomes 0.20875
- The Genome Aggregation Database (gnomAD) 0.18675
- The Genome Aggregation Database (gnomAD) 0.19180
- Exome Aggregation Consortium (ExAC) 0.24669
- Links
- ClinGen: CA126956
- Genetic Testing Registry (GTR): GTR000562560
- UniProtKB: P10635#VAR_008336
- OMIM: 124030.0005
- dbSNP: rs1065852
- VarSome
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Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Likely benign | 1 | criteria provided, single submitter | Mar 9, 2018 | RCV000603460.1 | |
| other | 1 | criteria provided, single submitter | Aug 6, 2018 | RCV000734607.3 | |
| drug response | 1 | criteria provided, single submitter | May 1, 2019 | RCV001030444.2 | |
| drug response | 1 | criteria provided, single submitter | May 1, 2019 | RCV001093717.2 | |
| drug response | 1 | no assertion criteria provided | May 18, 2015 | RCV000018389.23 | |
| drug response | 1 | no assertion criteria provided | Apr 28, 2018 | RCV001029560.2 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Likely benign
(Mar 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000730663.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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other
(Aug 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins NTD LLC (GA)
Accession: SCV000862761.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Sex: mixed
|
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|
drug response
(May 01, 2019)
|
criteria provided, single submitter
Method: curation
|
Deutetrabenazine response
Drug used for
Chorea
, Huntington disease
, and Tardive dyskinesia
Affected status: unknown
Allele origin:
germline
|
Medical Genetics Summaries
Accession: SCV001193762.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
CYP2D6*10 has decreased function: individuals with one decreased function and one no function allele (e.g., *4/*10) are intermediate metabolizers; individuals with two decreased function alleles … (more)
CYP2D6*10 has decreased function: individuals with one decreased function and one no function allele (e.g., *4/*10) are intermediate metabolizers; individuals with two decreased function alleles (e.g. *10/*10) are normal metabolizers or intermediate metabolizers (controversy remains). Therapeutic recommendations from professional societies state that the maximum dose of deutetrabenazine should not exceed 36 mg per day in individuals with 2 decreased function alleles (CYP2D6 poor metabolizers) to avoid abnormally high plasma levels due to reduced metabolic clearance. (less)
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drug response
(May 01, 2019)
|
criteria provided, single submitter
Method: curation
|
Tamoxifen response
Drug used for
Breast cancer
Affected status: unknown
Allele origin:
germline
|
Medical Genetics Summaries
Accession: SCV001250912.1
First in ClinVar: May 19, 2020 Last updated: May 19, 2020 |
Comment:
CYP2D6*10 has decreased function: individuals with one decreased function and one no function allele (e.g., *4/*10) are intermediate metabolizers; individuals with two decreased function alleles … (more)
CYP2D6*10 has decreased function: individuals with one decreased function and one no function allele (e.g., *4/*10) are intermediate metabolizers; individuals with two decreased function alleles (e.g. *10/*10) are normal metabolizers or intermediate metabolizers (controversy remains). Therapeutic recommendations from professional societies state that intermediate metabolizers may benefit less from tamoxifen therapy because they have lower concentrations of tamoxifen's major active metabolite, endoxifin, compared with normal metabolizers. For tamoxifen, CPIC prescribing recommendations for individuals with an activity score (AS) of 1.0 are allele dependent, based on the presence of the *10 allele: if a *10 allele is present, individuals are provided a 'moderate' recommendation; if *10 is NOT present, individuals are graded as 'optional' because the recommendations are primarily extrapolated from evidence generated from *10 individuals (i.e., limited data for clinical outcomes and pharmacokinetics for this group). (less)
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drug response
(May 18, 2015)
|
no assertion criteria provided
Method: literature only
|
DEBRISOQUINE, POOR METABOLISM OF
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038671.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
This allelic variant is also known as CYP2D6*10 or CYP2D6(J) or CYP2D6(Ch1, Ch2). Kagimoto et al. (1990) identified a 188C-T transition in exon 1 of … (more)
This allelic variant is also known as CYP2D6*10 or CYP2D6(J) or CYP2D6(Ch1, Ch2). Kagimoto et al. (1990) identified a 188C-T transition in exon 1 of the CYP2D6 gene, resulting in a pro34-to-ser (P34S) substitution as a cause of the debrisoquine poor metabolizer phenotype (608902). Nakamura et al. (2002) presented data strongly suggesting that catalytic activity as well thermal stability of the enzyme is affected by the P34S polymorphism. They proposed that thermal instability together with reduced intrinsic clearance of CYP2D6*10 is one reason for the finding of lower metabolic activities for drugs metabolized by CYP2D6 in Orientals, who have a high frequency of CYP2D6*10, compared with Caucasians. (less)
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drug response
(Apr 28, 2018)
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no assertion criteria provided
Method: research
|
Tramadol response
Affected status: yes
Allele origin:
somatic
|
Bruce Budowle Laboratory,University of North Texas Health Science Center
Accession: SCV001192346.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
Number of individuals with the variant: 32
|
Functional evidence
Help| Functional consequence | Method | Result | Submitter | Supporting information
(See all) |
|---|---|---|---|---|
|
Decreased function
|
Medical Genetics Summaries
Accession: SCV001193762.1
Submitted: (Nov 07, 2019)
|
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||
|
Decreased function
|
Medical Genetics Summaries
Accession: SCV001250912.1
Submitted: (Mar 06, 2020)
|
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Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Deutetrabenazine Therapy and <i>CYP2D6</i> Genotype | Dean L | - | 2019 | PMID: 31046213 |
| Tamoxifen Pharmacogenetics and Metabolism: Results From the Prospective CYPTAM Study. | Sanchez-Spitman A | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30676859 |
| Tamoxifen Therapy and <i>CYP2D6</i> Genotype | Dean L | - | 2019 | PMID: 28520357 |
| Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics. | Cronin-Fenton DP | Advances in pharmacology (San Diego, Calif.) | 2018 | PMID: 29801584 |
| Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease. | Dean M | Drug design, development and therapy | 2018 | PMID: 29497277 |
| Tamoxifen Metabolism and Efficacy in Breast Cancer: A Prospective Multicenter Trial. | Neven P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2018 | PMID: 29459457 |
| Tardive dyskinesia: Out of the shadows. | Hauser RA | Journal of the neurological sciences | 2018 | PMID: 29449008 |
| Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. | Goetz MP | Clinical pharmacology and therapeutics | 2018 | PMID: 29385237 |
| Impact of CYP2D6 polymorphisms on endoxifen concentrations and breast cancer outcomes. | Hwang GS | The pharmacogenomics journal | 2018 | PMID: 28762370 |
| Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients. | Helland T | Breast cancer research : BCR | 2017 | PMID: 29183390 |
| Impact of ABCB1 and CYP2D6 polymorphisms on tamoxifen treatment outcomes and adverse events in breast cancer patients. | Argalacsova S | Journal of B.U.ON. : official journal of the Balkan Union of Oncology | 2017 | PMID: 29135105 |
| Improved Prediction of Endoxifen Metabolism by CYP2D6 Genotype in Breast Cancer Patients Treated with Tamoxifen. | Schroth W | Frontiers in pharmacology | 2017 | PMID: 28955222 |
| CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study. | Hertz DL | Breast cancer research and treatment | 2017 | PMID: 28730340 |
| Don't think twice it's all right: tamoxifen and CYP2D6 genotyping in the treatment of breast cancer patients. | Damkier P | Pharmacogenomics | 2017 | PMID: 28592184 |
| Indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease. | Claassen DO | Journal of clinical movement disorders | 2017 | PMID: 28265459 |
| Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity. | Ahern TP | American journal of epidemiology | 2017 | PMID: 27988492 |
| Significant Effect of Polymorphisms in <i>CYP2D6</i> on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study. | Zembutsu H | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 27797974 |
| Should CYP2D6 be genotyped when treating with tamoxifen? | Del Re M | Pharmacogenomics | 2016 | PMID: 27883289 |
| Dopamine depleters in the treatment of hyperkinetic movement disorders. | Jankovic J | Expert opinion on pharmacotherapy | 2016 | PMID: 27819145 |
| Providing Balance in ASCO Clinical Practice Guidelines: CYP2D6 Genotyping and Tamoxifen Efficacy. | Goetz MP | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 27551126 |
| Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial. | Huntington Study Group. | JAMA | 2016 | PMID: 27380342 |
| Deutetrabenazine for Treatment of Chorea in Huntington Disease. | Geschwind MD | JAMA | 2016 | PMID: 27380339 |
| One step at a time: CYP2D6 guided tamoxifen treatment awaits convincing evidence of clinical validity. | Hertz DL | Pharmacogenomics | 2016 | PMID: 27249031 |
| Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity. | Hertz DL | The oncologist | 2016 | PMID: 27226358 |
| Pharmacogenetics of CYP2D6 and tamoxifen therapy: Light at the end of the tunnel? | Del Re M | Pharmacological research | 2016 | PMID: 27060675 |
| Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. | Saladores P | The pharmacogenomics journal | 2015 | PMID: 25091503 |
| Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen. | ter Heine R | British journal of clinical pharmacology | 2014 | PMID: 24697814 |
| Association between CYP2D6 genotypes and the clinical outcomes of adjuvant tamoxifen for breast cancer: a meta-analysis. | Jung JA | Pharmacogenomics | 2014 | PMID: 24329190 |
| CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. | Province MA | Clinical pharmacology and therapeutics | 2014 | PMID: 24060820 |
| Prediction of tamoxifen outcome by genetic variation of CYP2D6 in post-menopausal women with early breast cancer. | Brauch H | British journal of clinical pharmacology | 2014 | PMID: 24033728 |
| CYP2D6 genotype and tamoxifen activity: understanding interstudy variability in methodological quality. | Ratain MJ | Clinical pharmacology and therapeutics | 2013 | PMID: 23872831 |
| CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. | Regan MM | Journal of the National Cancer Institute | 2012 | PMID: 22395644 |
| CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. | Rae JM | Journal of the National Cancer Institute | 2012 | PMID: 22395643 |
| The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents. | Lu WJ | Breast cancer research and treatment | 2012 | PMID: 21814747 |
| Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. | Schroth W | JAMA | 2009 | PMID: 19809024 |
| Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. | Lim HS | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2007 | PMID: 17761971 |
| Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. | Desta Z | The Journal of pharmacology and experimental therapeutics | 2004 | PMID: 15159443 |
| CYP2D6.10 present in human liver microsomes shows low catalytic activity and thermal stability. | Nakamura K | Biochemical and biophysical research communications | 2002 | PMID: 12051754 |
| 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. | Kagimoto M | The Journal of biological chemistry | 1990 | PMID: 2211621 |
| DailyMed Drug Label, AUSTEDO- deutetrabenazine tablet, coated, deutetrabenazine kit, 2021 | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP2D6 | - | - | - | - |
| https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7ea3c60a-45c7-44cc-afc2-d87fa53993c0 | - | - | - | - |
| https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7ee3d3d2-85d1-4018-8e70-5ed8a64ae1f0 | - | - | - | - |
Text-mined citations for rs1065852...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jun 24, 2022