Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor metabolizers (2 no function alleles, e.g., *4/*4).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.
ClinVar Genomic variation as it relates to human health
CYP2D6*4
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely benign; drug response; other
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
CYP2D6*4
Variation ID: 16889 Accession: VCV000016889.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q13.2 22: 42128945 (GRCh38) [ NCBI UCSC ] 22: 42524947 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 May 19, 2020 May 1, 2019 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000106.6:c.506-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001025161.3:c.353-1G>A splice acceptor NC_000022.11:g.42128945C>T NC_000022.10:g.42524947C>T NG_008376.4:g.6866G>A LRG_303:g.6866G>A LRG_303t1:c.506-1G>A - Protein change
- -
- Other names
-
1846G>A
NM_000106.5(CYP2D6):c.506-1G>A
IVSDS3, G-A, +1
- Canonical SPDI
- NC_000022.11:42128944:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
No function
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.09305 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.09305
1000 Genomes Project 30x 0.09416
The Genome Aggregation Database (gnomAD), exomes 0.13858
Trans-Omics for Precision Medicine (TOPMed) 0.14281
The Genome Aggregation Database (gnomAD) 0.14340
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.15105
Exome Aggregation Consortium (ExAC) 0.17076
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CYP2D6 | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
245 | 336 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| drug response (1) |
no assertion criteria provided
|
May 18, 2015 | RCV000018385.31 | |
| other (1) |
criteria provided, single submitter
|
Aug 6, 2018 | RCV000342450.13 | |
| Likely benign (1) |
criteria provided, single submitter
|
Mar 9, 2018 | RCV000613767.9 | |
| drug response (1) |
no assertion criteria provided
|
Apr 28, 2018 | RCV001028774.10 | |
| drug response (1) |
criteria provided, single submitter
|
May 1, 2019 | RCV001030442.10 | |
| drug response (1) |
criteria provided, single submitter
|
May 1, 2019 | RCV001093714.10 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
other
(Aug 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331716.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 97
Sex: mixed
|
|
|
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: SCV001193760.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor … (more)
Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor metabolizers (2 no function alleles, e.g., *4/*4).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)
|
|
|
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: SCV001250909.1
First in ClinVar: May 19, 2020 Last updated: May 19, 2020 |
Comment:
Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor … (more)
Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor metabolizers (2 no function alleles, e.g., *4/*4). Currently, there is no consensus on therapeutic guidelines for tamoxifen based on CYP2D6 genotype. Professional societies suggest that poor metabolizers may benefit less from tamoxifen therapy because they have lower concentrations of tamoxifen's major active metabolite, endoxifin, compared with normal metabolizers. (less)
|
|
|
Likely benign
(Mar 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000730662.1
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)
|
|
|
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: SCV000038667.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
This allelic variant is also known as CYP2D6*4 or CYP2D6(B). In 20 individuals with poor metabolism of debrisoquine (608902), Gough et al. (1990) identified a … (more)
This allelic variant is also known as CYP2D6*4 or CYP2D6(B). In 20 individuals with poor metabolism of debrisoquine (608902), Gough et al. (1990) identified a G-to-A transition at the first nucleotide of exon 4 in the CYP2D6 gene, resulting in a shift of the splice site and introduction of a premature termination codon. The mutant protein had no residual activity. Gough et al. (1990) presented preliminary data suggesting a reduction in the proportion of poor metabolizers among patients with lung or bladder cancer. In leukocyte DNA of an individual who was deficient in debrisoquine metabolism, Hanioka et al. (1990) identified a 1934G-A transition at the junction of the third intron and fourth exon, resulting in an aberrant 3-prime splice recognition site and an mRNA with a single basepair deletion. The disrupted mRNA leads to a truncated protein without functional activity. The patient studied was a compound heterozygote: the allele with the 1934G-A mutation was identified by a 44-kb XbaI restriction fragment; the second allele was a complete deletion of the CYP2D6 gene (124030.0002). The dextromethorphan urinary metabolite ratio in this patient was 9.7, which is operationally defined as a poor metabolizer of debrisoquine. Kagimoto et al. (1990) likewise concluded that the mutation at the 3-prime splice site of intron 3 is a common cause of the poor metabolizer phenotype. Chen et al. (1995) found that Alzheimer disease (104300) patients who were either heterozygous or homozygous for the CYP2D6*4 allele had a smaller decline of the synaptic markers choline acetyltransferase (118490) and synaptophysin (313475) in the frontal cortex than those who did not. Senile plaques neurofibrillary tangles were not significantly affected. The authors had earlier shown an association of the CYP2D6*4 mutant allele with Lewy body formation (127750). The findings suggested different mechanisms of neurodegeneration in the 2 disorders. (less)
|
|
|
drug response
(Apr 28, 2018)
|
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: SCV001191560.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
Number of individuals with the variant: 32
|
Comment:
Comment:
Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor metabolizers (2 no function alleles, e.g., *4/*4). Currently, there is no consensus on therapeutic guidelines for tamoxifen based on CYP2D6 genotype. Professional societies suggest that poor metabolizers may benefit less from tamoxifen therapy because they have lower concentrations of tamoxifen's major active metabolite, endoxifin, compared with normal metabolizers.
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 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.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
No function
|
Medical Genetics Summaries
Accession: SCV001193760.1
|
|
||
|
No function
|
Medical Genetics Summaries
Accession: SCV001250909.1
|
|
Comment:
Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor metabolizers (2 no function alleles, e.g., *4/*4).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.
Comment:
Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor metabolizers (2 no function alleles, e.g., *4/*4). Currently, there is no consensus on therapeutic guidelines for tamoxifen based on CYP2D6 genotype. Professional societies suggest that poor metabolizers may benefit less from tamoxifen therapy because they have lower concentrations of tamoxifen's major active metabolite, endoxifin, compared with normal metabolizers.
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 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 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 CYP2D6 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 |
| The CYP2D6B allele is associated with a milder synaptic pathology in Alzheimer's disease. | Chen X | Annals of neurology | 1995 | PMID: 7574463 |
| 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 |
| The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934----A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3' splice recognition site. | Hanioka N | American journal of human genetics | 1990 | PMID: 1978565 |
| Identification of the primary gene defect at the cytochrome P450 CYP2D locus. | Gough AC | Nature | 1990 | PMID: 1978251 |
| 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=7ee3d3d2-85d1-4018-8e70-5ed8a64ae1f0 | - | - | - | - |
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Text-mined citations for rs3892097 ...
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 Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.