PharmCAT Report

Titleexample
Date createdApril 26, 2018
Versionv0.3.0-16-g455b909

Pre-release software - For code testing only

This software has not been officially released. You should only be using this software to evaluate whether the PharmCAT executable will compile and run properly on your system. The content of the reporting is not yet complete so results will change. The user recognizes they are using PharmCAT at their own risk.
Disclaimer: The PharmCAT report is only able to generate recommendations based on the information imported into the software. The gene and variant information for all reported sections are interpreted directly from the uploaded vcf file. The user recognizes they are using PharmCAT at their own risk. For a detailed disclaimer see section IV.

Sections

  1. Genotype Summary
  2. CPIC Recommendations
  3. Allele Call Details
  4. Disclaimers

Genotype Summary

Genotypes called: 12 / 12

Drugs a Gene Genotype Allele Functionality b Phenotype b Missing Variant Input c
CFTR
No CPIC variants found
N/A
N/A
No
CYP2C19
*1/*1
Two normal function alleles
Normal Metabolizer
No
CYP2C9
*1/*1
Two normal function alleles
Normal Metabolizer
No
CYP2D6
*3/*4
Two no function alleles
Poor Metabolizer
N/A
CYP3A5
*1/*1
Two normal function alleles
Normal Metabolizer
No
CYP4F2
*1/*1
Two normal function alleles
N/A
No
DPYD
No CPIC decreased or no function variant with strong or moderate evidence found
Two normal function alleles
Normal Metabolizer (Activity Score=2)
No
IFNL3
rs12979860C/rs12979860C
N/A
N/A
No
SLCO1B1
*1A/*1A
Two normal function alleles
Normal Function
No
TPMT
*1/*1
Two normal function alleles
Normal Metabolizer
No
UGT1A1
*1/*1
Two normal function alleles
Normal Metabolizer
No
VKORC1
-1639A/-1639A
N/A
N/A
No
a The drugs are colored to indicate whether CPIC recommends a prescribing change based on the given genotype; highlighting is not based on CPIC classification of recommendation. When multiple diplotypes are possible for a gene, the drug is highlighted according to the highest level of prescribing change. Red indicates a prescribing change is recommended for the given diplotype. That is, the recommendation is different than ‘use label recommendation’ or ‘use recommended starting dose’, except for ivacaftor. Orange indicates possible prescribing changes depending on additional information, e.g. pediatrics vs. adult, or the specific number of CYP2D6 normal alleles present (copy number). Green indicates that there is no CPIC recommended prescribing change for the given diplotype, except for ivacaftor. Blue indicates the specific guideline must be consulted because a CPIC recommended action cannot be provided based solely on diplotype (eg. warfarin and ribavirin/peginterferon).
b Allele functionality and phenotype terms are based on the CPIC term standardization project, PMID:27441996. Guidelines published prior use the term 'extensive' instead of 'normal' metabolizer. CYP2C19*1/*17 is now classified as rapid metabolizer. Guidelines published prior group CYP2C19*1/*17 together with *17/*17 as ultrarapid metabolizer.
c Indicates alleles not considered for the genotype calls due to missing variant information, please see Allele calls section. Alleles that could not be considered due to missing input might change the metabolizer phenotype and possible CPIC recommendation.
Check the allele call details for this gene for more details about this call.
For a full list of disclaimers and limitations see the Disclaimer section.

CPIC Recommendations

amitriptyline

The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2C19:Normal Function/Normal Function
CYP2D6:No Function/No Function
PhenotypeCYP2D6 Poor Metabolizer CYP2C19 Normal Metabolizer
Implications

For CYP2D6:

Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.

For CYP2C19:

Normal metabolism of tertiary amines.

Recommendations

Avoid amitriptyline use. If amitriptyline is warranted, consider 50% reduction of recommended starting dose.

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended. Patients may receive an initial low dose of TCAs, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression.

Classification of RecommendationStrong
Classification of recommendation might differ based on the availabilty of CYP2D6 or CYP2C19 genotypes only or a combination of CYP2D6 and CYP2C19 genotypes; see full guideline at cpicpgx.org.

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.12.14

atazanavir

The CPIC dosing guideline recommends considering advising individuals who carry two decreased function UGT1A1 alleles about a substantial likelihood of developing jaundice, which may cause non-adherence. The dosing guideline recommends that alternative agents be considered if the risk of non-adherence due to jaundice is high. The risk of discontinuation is low and very low for individuals carrying one, or no decreased function UGT1A1 alleles, respectively.

The official guideline can be found on the CPIC website.

Unphased data: all variant alleles found are listed based on the vcf input and the UGT1A1 definition table. Phased data: the subject’s phased UGT1A1 genotype is listed. The CPIC recommendations are provided based on an exception logic. UGT1A1*28 and *80 are assumed in cis for unphased data, see http://pharmcat.org/ and the UGT1A1 gene section for details on *80.
TypeAnnotation
Allele FunctionalityUGT1A1:Normal Function/Normal Function
PhenotypeNormal Metabolizer
Implications

Reference UGT1A1 activity; very low likelihood of bilirubin-related discontinuation of atazanavir.

“Reference” function refers to the UGT1A1 allele to which other alleles are compared.

Recommendations

There is no need to avoid prescribing of atazanavir based on UGT1A1 genetic test result.

Inform the patient that some patients stop atazanavir because of jaundice (yellow eyes and skin), but that this patient’s genotype makes this unlikely (less than about a 1 in 20 chance of stopping atazanavir because of jaundice).

Classification of RecommendationStrong
These recommendations are for the use of atazanavir (boosted with either ritonavir or cobicistat) by UGT1A1 phenotype. All studies correlating UGT1A1 genotypes with atazanavir adverse events have involved ritonavir boosting. However, concentration-time profiles are equivalent when boosted with either cobicistat or ritonavir, and bilirubin-related adverse events including discontinuation of atazanavir occur in a similar percentage of patients prescribed atazanavir with cobicistat or ritonavir. Associations between UGT1A1 genotype, bilirubin elevations, and atazanavir discontinuation therefore almost certainly translate to atazanavir/cobicistat.

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2015.09.18

azathioprine

Consider an alternate agent or extreme dose reduction of azathioprine for patients with low or deficient TPMT activity. Start at 30-70% of target dose for patients with intermediate enzyme activity.

The official guideline can be found on the CPIC website.

TypeAnnotation
Allele FunctionalityTPMT:Normal Function/Normal Function
PhenotypeNormal Metabolizer
Implications

Lower concentrations of TGN metabolites, higher methylTIMP, this is the "normal" pattern

Recommendations

Start with normal starting dose (e.g., 2-3 mg/kg/d) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady state after each dose adjustment.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.05.10

capecitabine

The CPIC Dosing Guideline for 5-fluorouracil and capecitabine recommends an alternative drug for patients who are DPYD poor metabolizers with an activity score of 0. In those who are poor metabolizers with an activity score of 0.5, an alternative drug is also recommended, but if this is not considered a suitable therapeutic option, 5-fluorouracil or capecitabine should be administered at a strongly reduced dose with early therapeutic drug monitoring. Patients who are intermediate metabolizers with an activity score of 1 or 1.5 should receive a dose reduction of 50% and 25%-50%, respectively.

The official guideline can be found on the CPIC website.

The 2017 CPIC DPYD guideline update includes normal function variants with strong, moderate or in vitro data only evidence. These variants are not included in the PharmCAT DPYD gene definition table. The CPIC DPYD functionality table includes further no and decreased function variants with 'In vitro data only and/or limited clinical/ex vivo data' evidence. According to the guideline, to date, there are no studies linking the variants listed in the “in vitro data only and/or limited clinical/ex vivo data” category as decreased or no function variants directly to toxicity related to fluoropyrimidines and therefore, these variants are not specifically included in the CPIC recommendations. These variants are not included in the PharmCAT DPYD gene definition table. Refer to the DPYD gene section for a list of these variants.
TypeAnnotation
Allele FunctionalityDPYD:Normal Function/Normal Function
PhenotypeNormal Metabolizer (Activity Score=2)
Implications

Normal DPD activity and "normal" risk for fluoropyrimidine toxicity.

Recommendations

Based on genotype, there is no indication to change dose or therapy. Use label-recommended dosage and administration.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2017.11.13

escitalopram, citalopram

The CPIC Dosing Guideline for the selective serotonin reuptake inhibitors citalopram and escitalopram recommends an alternative drug not predominantly metabolized by CYP2C19 for CYP2C19 ultrarapid metabolizers. For CYP2C19 poor metabolizers, consider a 50% reduction of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19.

The official guideline can be found on the CPIC website.

TypeAnnotation
Allele FunctionalityCYP2C19:Normal Function/Normal Function
PhenotypeNormal Metabolizer
Implications

Normal metabolism

Recommendations

Initiate therapy with recommended starting dose.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2015.05.11

clomipramine

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline and CYP2C19, CYP2D6 to other tricyclics including clomipramine. The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2C19:Normal Function/Normal Function
CYP2D6:No Function/No Function
PhenotypeCYP2D6 Poor Metabolizer CYP2C19 Normal Metabolizer
Implications

For CYP2D6:

Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.

For CYP2C19:

Normal metabolism of tertiary amines.

Recommendations

The dosing recommendations are based on studies focusing on amitriptyline. Because tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply these guidelines to other tertiary amines including clomipramine, doxepin, imipramine and trimipramine.

Avoid TCA use. If TCAs are warranted, consider 50% reduction of recommended starting dose.

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended. Patients may receive an initial low dose of TCAs, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression.

Classification of RecommendationOptional
Classification of recommendation might differ based on the availabilty of CYP2D6 or CYP2C19 genotypes only or a combination of CYP2D6 and CYP2C19 genotypes; see full guideline at cpicpgx.org.

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.12.14

clopidogrel

The CPIC Dosing Guideline for clopidogrel recommends an alternative antiplatelet therapy (e.g., prasugrel, ticagrelor) for CYP2C19 poor or intermediate metabolizers if there is no contraindication.

The official guideline can be found on the CPIC website.

TypeAnnotation
Allele FunctionalityCYP2C19:Normal Function/Normal Function
PhenotypeNormal Metabolizer
Implications

Normal platelet inhibition; normal residual platelet aggregation

Recommendations

Clopidogrel - label recommended dosage and administration

Classification of RecommendationStrong
Antiplatelet therapy recommendations are based on CYP2C19 status when considering clopidogrel for acute coronary syndrome (ACS patients undergoing percutaneous coronary intervention (PCI)). CPIC guidelines reflect the alleles/genotypes known and considered by the guideline authors for inclusion by the time of publication. CPIC guidelines are periodically updated - see cpicpgx.org.

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2013.05.22

codeine

Alternate analgesics are recommended for CYP2D6 ultrarapid and poor metabolizers. A label recommended age- or weight-specific codeine dose is warranted for CYP2D6 extensive and intermediate metabolizers.

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2D6:No Function/No Function
PhenotypePoor Metabolizer
Activity Score

0

Implications

Greatly reduced morphine formation following codeine administration, leading to insufficient pain relief

Recommendations

Avoid codeine use due to lack of efficacy.

Considerations for alternative opioids: Alternatives that are not affected by this CYP2D6 phenotype include morphine and non-opioid analgesics. Tramadol, and to a lesser extent hydrocodone and oxycodone, are not good alternatives because their metabolism is affected by CYP2D6 activity; these agents should be avoided. There is substantial evidence for decreased efficacy of tramadol in poor metabolizers and a single case report of toxicity in an ultrarapid metabolizer with renal impairment following tramadol post-surgery. Use of other analgesics in CYP2D6 poor and ultrarapid metabolizers may therefore be preferable. Some other opioid analgesics are metabolized by CYP2D6, such as hydrocodone and oxycodone. To avoid treatment complications, opioids that are not metabolized by CYP2D6, including morphine, oxymorphone, buprenorphine, fentanyl, methadone and hydromorphone, along with non-opioid analgesics, may be considered as alternatives for use in CYP2D6 poor and ultrarapid metabolizers.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2017.05.02

desipramine

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline/nortriptyline and CYP2C19, CYP2D6 to other tricyclics including desipramine. The CPIC Dosing Guideline update for nortriptyline recommends a 25% dose reduction for CYP2D6 intermediate metabolizers. For CYP2D6 ultrarapid or poor metabolizers, an alternative drug should be considered. If nortriptyline is warranted, consider a 50% dose reduction in CYP2D6 poor metabolizers.

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2D6:No Function/No Function
PhenotypePoor Metabolizer
Activity Score

0

Implications

Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.

Recommendations

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider 50% reduction of recommended starting dose.g Utilize therapeutic drug monitoring to guide dose adjustments.

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression.

Classification of RecommendationOptional

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.12.14

doxepin

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline and CYP2C19, CYP2D6 to other tricyclics including doxepin. The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2C19:Normal Function/Normal Function
CYP2D6:No Function/No Function
PhenotypeCYP2D6 Poor Metabolizer CYP2C19 Normal Metabolizer
Implications

For CYP2D6:

Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.

For CYP2C19:

Normal metabolism of tertiary amines.

Recommendations

The dosing recommendations are based on studies focusing on amitriptyline. Because tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply these guidelines to other tertiary amines including clomipramine, doxepin, imipramine and trimipramine.

Avoid TCA use. If TCAs are warranted, consider 50% reduction of recommended starting dose.

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended. Patients may receive an initial low dose of TCAs, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression.

Classification of RecommendationOptional
Classification of recommendation might differ based on the availabilty of CYP2D6 or CYP2C19 genotypes only or a combination of CYP2D6 and CYP2C19 genotypes; see full guideline at cpicpgx.org.

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.12.14

fluorouracil

The CPIC Dosing Guideline for 5-fluorouracil and capecitabine recommends an alternative drug for patients who are DPYD poor metabolizers with an activity score of 0. In those who are poor metabolizers with an activity score of 0.5, an alternative drug is also recommended, but if this is not considered a suitable therapeutic option, 5-fluorouracil or capecitabine should be administered at a strongly reduced dose with early therapeutic drug monitoring. Patients who are intermediate metabolizers with an activity score of 1 or 1.5 should receive a dose reduction of 50% and 25%-50%, respectively.

The official guideline can be found on the CPIC website.

The 2017 CPIC DPYD guideline update includes normal function variants with strong, moderate or in vitro data only evidence. These variants are not included in the PharmCAT DPYD gene definition table. The CPIC DPYD functionality table includes further no and decreased function variants with 'In vitro data only and/or limited clinical/ex vivo data' evidence. According to the guideline, to date, there are no studies linking the variants listed in the “in vitro data only and/or limited clinical/ex vivo data” category as decreased or no function variants directly to toxicity related to fluoropyrimidines and therefore, these variants are not specifically included in the CPIC recommendations. These variants are not included in the PharmCAT DPYD gene definition table. Refer to the DPYD gene section for a list of these variants.
TypeAnnotation
Allele FunctionalityDPYD:Normal Function/Normal Function
PhenotypeNormal Metabolizer (Activity Score=2)
Implications

Normal DPD activity and "normal" risk for fluoropyrimidine toxicity.

Recommendations

Based on genotype, there is no indication to change dose or therapy. Use label-recommended dosage and administration.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2017.11.28

fluvoxamine

The CPIC Dosing Guideline for the selective serotonin reuptake inhibitor fluvoxamine recommends to consider a 25-50% reduction of recommended starting dose and titrate to response or use an alternative drug not metabolized by CYP2D6 for CYP2D6 poor metabolizers.

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2D6:No Function/No Function
PhenotypePoor Metabolizer
Activity Score

0

Implications

Greatly reduced metabolism when compared to normal metabolizers. Higher plasma concentrations may increase the probability of side effects.

Recommendations

Consider a 25-50% reduction of recommended starting dose and titrate to response or use an alternative drug not metabolized by CYP2D6.

Dose extrapolations based on differences in pharmacokinetic parameters between phenotype groups suggest a 30% dose reduction of fluvoxamine. However, a 30% decrease in dose may not be feasible given the dosage forms, therefore, decreasing the starting dose of fluvoxamine by 25-50% should be considered. Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

Classification of RecommendationOptional

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2015.05.08

imipramine

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline and CYP2C19, CYP2D6 to other tricyclics including imipramine. The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2C19:Normal Function/Normal Function
CYP2D6:No Function/No Function
PhenotypeCYP2D6 Poor Metabolizer CYP2C19 Normal Metabolizer
Implications

For CYP2D6:

Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.

For CYP2C19:

Normal metabolism of tertiary amines.

Recommendations

The dosing recommendations are based on studies focusing on amitriptyline. Because tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply these guidelines to other tertiary amines including clomipramine, doxepin, imipramine and trimipramine.

Avoid TCA use. If TCAs are warranted, consider 50% reduction of recommended starting dose.

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended. Patients may receive an initial low dose of TCAs, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression.

Classification of RecommendationOptional
Classification of recommendation might differ based on the availabilty of CYP2D6 or CYP2C19 genotypes only or a combination of CYP2D6 and CYP2C19 genotypes; see full guideline at cpicpgx.org.

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.12.14

ivacaftor

Ivacaftor treatment is recommended only in cystic fibrosis (CF) patients that are either homozygous or heterozygous for certain CFTR variants. See full guideline for disclaimers, further details and supporting evidence.

The official guideline can be found on the CPIC website.

TypeAnnotation
Recommendations

This guideline does not contain recommendations for this allele combination.

Classification of RecommendationN/A

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2017.06.02

mercaptopurine

Start with reduced doses of mercaptopurine for patients with one nonfunctional TPMT allele, or drastically reduced doses for patients with malignancy and two nonfunctional alleles; adjust dose based on degree of myelosuppression and disease-specific guidelines. Consider alternative nonthiopurine immunosuppressant therapy for patients with nonmalignant conditions and two nonfunctional alleles.

The official guideline can be found on the CPIC website.

TypeAnnotation
Allele FunctionalityTPMT:Normal Function/Normal Function
PhenotypeNormal Metabolizer
Implications

Lower concentrations of TGN metabolites, higher methylTIMP, this is the "normal" pattern

Recommendations

Start with normal starting dose (e.g., 75 mg/m2/d or 1.5 mg/kg/d) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow 2 weeks to reach steady state after each dose adjustment.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.05.10

nortriptyline

The CPIC Dosing Guideline update for nortriptyline recommends a 25% dose reduction for CYP2D6 intermediate metabolizers. For CYP2D6 ultrarapid or poor metabolizers, an alternative drug should be considered. If nortriptyline is warranted, consider a 50% dose reduction in CYP2D6 poor metabolizers.

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2D6:No Function/No Function
PhenotypePoor Metabolizer
Activity Score

0

Implications

Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.

Recommendations

Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider 50% reduction of recommended starting dose.g Utilize therapeutic drug monitoring to guide dose adjustments.

Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.12.14

ondansetron

The CPIC dosing guideline for ondansetron recommends selecting an alternate drug for CYP2D6 ultrarapid metabolizers. It is recommended that the alternate drug not be predominantly metabolized by CYP2D6 (eg. granisetron).

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2D6:No Function/No Function
PhenotypePoor Metabolizer
Activity Score

0

Implications

Very limited data available for CYP2D6 poor metabolizers

Recommendations

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

Classification of RecommendationNo recommendation

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.12.23

paroxetine

The CPIC Dosing Guideline for the selective serotonin reuptake inhibitor paroxetine recommends an alternative drug not predominantly metabolized by CYP2D6 for CYP2D6 ultrarapid metabolizers and for CYP2D6 poor metabolizers. For CYP2D6 poor metabolizers, if paroxetine use is warranted, consider a 50% reduction of recommended starting dose and titrate to response.

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2D6:No Function/No Function
PhenotypePoor Metabolizer
Activity Score

0

Implications

Greatly reduced metabolism when compared to normal metabolizers. Higher plasma concentrations may increase the probability of side effects.

Recommendations

Select alternative drug not predominantly metabolized by CYP2D6 or if paroxetine use warranted, consider a 50% reduction of recommended starting dose and titrate to response.

Drug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

Classification of RecommendationOptional

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2015.05.08

peginterferon alfa-2a, peginterferon alfa-2b, ribavirin

IFNL3 (IL28B) variation (rs12979860) is the strongest baseline predictor of response to PEG-interferon-alpha-containing regimens in HCV genotype 1 patients. Patients with the favorable response genotype (rs12979860 CC) have increased likelihood of response (higher SVR rate) to PEG-interferon-alpha-containing regimens as compared to patients with unfavorable response genotype (rs12979860 CT or TT). Consider implications before initiating PEG-IFN alpha and RBV containing regimens.

The official guideline can be found on the CPIC website.

TypeAnnotation
Implications

For patients treated with PEG-IFN alpha and RBV alone, approximately 70% chance for sustained virologic response (SVR, defined by undetectable serum viral RNA 12-24 weeks after the end of treatment) after 48 weeks of treatment. Consider implications before initiating PEG-IFN alpha and RBV containing regimens.

For patients treated with protease inhibitor combinations with PEG-IFN alpha and RBV therapy, approximately 90% chance for SVR after 24-48 weeks of treatment. Approximately 80-90% of patients are eligible for shortened therapy (24-28 weeks vs. 48 weeks, with patients receiving boceprevir are eligible for 24-28 weeks instead of the standard 48 weeks if HCV RNA is undetectable by week eight. Patients receiving telaprevir are eligible for 24 weeks of therapy instead of the standard 48 weeks if HCV RNA is undetectable by week four.). Weighs in favor of using PEG-IFN alpha and RBV containing regimens.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.02.25

phenytoin

Phenytoin is contraindicated in individuals with the HLA-B*15:02 variant allele ("HLA-B*15:02-positive") due to significantly increased risk of phenytoin-induced cutaneous adverse reactions of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Additionally, patients with the CYP2C9 poor metabolizer phenotype may require reduced doses of phenytoin.

The official guideline can be found on the CPIC website.

The displayed recommendation for CYP2C9 and phenytoin is ONLY valid for non-carriers of the HLA-B*15:02 high-risk allele. PharmCAT does not interpret HLA carrier status. Phenytoin is contraindicated in individuals with the HLA-B*15:02 variant allele ("HLA-B*15:02-positive") due to significantly increased risk of phenytoin-induced cutaneous adverse reactions of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). In HLA-B*15:02 carriers, carbamazepine should not be used as an alternative. Alternative medications such as oxcarbazepine, eslicarbazepine acetate, and lamotrigine have some evidence linking SJS/TEN with the HLA-B*15:02 allele, and thus caution should be used in choosing alternatives to phenytoin.
TypeAnnotation
Allele FunctionalityCYP2C9:Normal Function/Normal Function
HLA-B:Absence/Absence
PhenotypeCYP2C9 Normal Metabolizer
Implications

Normal phenytoin metabolism.

Recommendations

Initiate therapy with recommended maintenance dose (based on patient’s clinical characteristics).

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2014.08.05

sertraline

The CPIC Dosing Guideline for the selective serotonin reuptake inhibitor sertraline recommends to consider a 50% reduction of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19 for CYP2C19 poor metabolizers.

The official guideline can be found on the CPIC website.

TypeAnnotation
Allele FunctionalityCYP2C19:Normal Function/Normal Function
PhenotypeNormal Metabolizer
Implications

Normal metabolism

Recommendations

Initiate therapy with recommended starting dose.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2015.05.08

simvastatin

The FDA recommends against 80mg daily simvastatin dosage. In patients with the C allele at SLCO1B1 rs4149056, there are modest increases in myopathy risk even at lower simvastatin doses (40mg daily); if optimal efficacy is not achieved with a lower dose, alternate agents should be considered.

The official guideline can be found on the CPIC website.

SLCO1B1 star allele nomenclature represents various SNPs alone or in combination. The SLCO1B1 genotype (star nomenclature) will be displayed if determinable with the provided VCF based on the SLCO1B1 star allele definition published by CPIC and recommendations are provided based on the genotype.

In case no genotype can be determined, recommendations are based on the rs4149056 genotype alone as per guideline. The minor C allele at rs4149056 is contained in SLCO1B1*5 (rs4149056 alone) as well as the *15 and *17 alleles, and is associated with lower plasma clearance of simvastatin. The magnitude of this effect is similar for *5, *15, and *17 alleles. A number of SLCO1B1 alleles (*2, *3, *6, *9, *10, *23, *31) are classified by CPIC as 'possible decreased function' alleles. These alleles are not accounted for in the recommendation based on the rs4149056 genotype. Carriage of additional variants is possible.
TypeAnnotation
Allele FunctionalitySLCO1B1:Normal Function/Normal Function
PhenotypeNormal Function
Implications

Normal myopathy risk

Recommendations

Prescribe desired starting dose and adjust doses of simvastatin based on disease-specific guidelines

Classification of RecommendationStrong
In all cases, the potential for drug-drug interaction should be evaluated prior to initiating a prescription. FDA recommends against 80mg of simvastatin (unless already tolerated for 12 months).

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2014.06.30

tacrolimus

The CPIC dosing guideline for tacrolimus recommends increasing the starting dose by 1.5 to 2 times the recommended starting dose in patients who are CYP3A5 intermediate or extensive metabolizers, though total starting dose should not exceed 0.3 mg/kg/day. Therapeutic drug monitoring should also be used to guide dose adjustments.

The official guideline can be found on the CPIC website.

TypeAnnotation
Allele FunctionalityCYP3A5:Normal Function/Normal Function
PhenotypeNormal Metabolizer
Implications

Lower dose-adjusted trough concentrations of tacrolimus and decreased chance of achieving target tacrolimus concentrations.

Recommendations

Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments.

Further dose adjustments or selection of alternative therapy may be necessary because of other clinical factors (e.g., medication interactions, or hepatic function).

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2015.08.11

thioguanine

Start with reduced doses of thioguanine for patients with one nonfunctional TPMT allele, or drastically reduced doses for patients with malignancy and two nonfunctional alleles; adjust dose based on degree of myelosuppression and disease-specific guidelines. Consider alternative nonthiopurine immunosuppressant therapy for patients with nonmalignant conditions and two nonfunctional alleles.

The official guideline can be found on the CPIC website.

TypeAnnotation
Allele FunctionalityTPMT:Normal Function/Normal Function
PhenotypeNormal Metabolizer
Implications

Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10x higher than TGN after mercaptopurine or azathioprine

Recommendations

Start with normal starting dose. Adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady state after each dose adjustment.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.05.10

trimipramine

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline and CYP2C19, CYP2D6 to other tricyclics including trimipramine. The CPIC Dosing Guideline update for amitriptyline recommends an alternative drug for CYP2D6 ultrarapid or poor metabolizers and CYP2C19 ultrarapid, rapid or poor metabolizers. If amitriptyline is warranted, consider a 50% dose reduction in CYP2D6 or CYP2C19 poor metabolizers. For CYP2D6 intermediate metabolizers, a 25% dose reduction should be considered.

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2C19:Normal Function/Normal Function
CYP2D6:No Function/No Function
PhenotypeCYP2D6 Poor Metabolizer CYP2C19 Normal Metabolizer
Implications

For CYP2D6:

Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.

For CYP2C19:

Normal metabolism of tertiary amines.

Recommendations

The dosing recommendations are based on studies focusing on amitriptyline. Because tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply these guidelines to other tertiary amines including clomipramine, doxepin, imipramine and trimipramine.

Avoid TCA use. If TCAs are warranted, consider 50% reduction of recommended starting dose.

Utilizing therapeutic drug monitoring if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate or poor metabolism in combination with CYP2C19 ultrarapid, intermediate or poor metabolism is strongly recommended. Patients may receive an initial low dose of TCAs, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose. Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression.

Classification of RecommendationOptional
Classification of recommendation might differ based on the availabilty of CYP2D6 or CYP2C19 genotypes only or a combination of CYP2D6 and CYP2C19 genotypes; see full guideline at cpicpgx.org.

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.12.14

tropisetron

The CPIC dosing guideline for tropisetron recommends selecting an alternate drug for CYP2D6 ultrarapid metabolizers. It is recommended that the alternate drug not be predominantly metabolized by CYP2D6 (eg. granisetron).

The official guideline can be found on the CPIC website.

CYP2D6: *3/*4 (from Astrolabe)
TypeAnnotation
Allele FunctionalityCYP2D6:No Function/No Function
PhenotypePoor Metabolizer
Activity Score

0

Implications

Very limited data available for CYP2D6 poor metabolizers

Recommendations

Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.

Classification of RecommendationNo recommendation

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.12.23

voriconazole

The CPIC dosing guideline for voriconazole recommends selecting an alternative agent that is not dependent on CYP2C19 metabolism in adults who are CYP2C19 ultrarapid metabolizers, rapid metabolizers or poor metabolizers. In pediatric patients, an alternative agent should be used in patients who are ultrarapid metabolizers or poor metabolizers. In pediatric rapid metabolizers, therapy should be initiated at recommended standard case dosing, then therapeutic dosing monitoring should be used to titrate dose to therapeutic trough concentrations.

The official guideline can be found on the CPIC website.

TypeAnnotation
Allele FunctionalityCYP2C19:Normal Function/Normal Function
PhenotypeNormal Metabolizer
Implications

Normal voriconazole metabolism

Recommendations

For pediatric or adult patients: initiate therapy with recommended standard of care dosing.

Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, TDM, and comorbidities.

Classification of RecommendationStrong

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2016.12.02

warfarin

The updated guideline for pharmacogenetics-guided warfarin dosing is published by the Clinical Pharmacogenetics Implementation Consortium. The recommendations for dosing are for adult and pediatric patients that are specific to continental ancestry, and are based on genotypes from CYP2C9, VKORC1, CYP4F2, and rs12777823.

The official guideline can be found on the CPIC website.

Please follow the flow chart in figure 2 of the CPIC warfarin guideline to determine the appropriate dosing recommendation.
Figure 2 from the CPIC guideline for warfarin
The CPIC warfarin guideline only considers a single SNV in VKORC1 (rs9923231), which is found in the highest frequency in Caucasians and extremely low frequency in those of African descent. While other functional variants in VKORC1 have been observed in much higher frequencies in some populations, there are currently no CPIC recommendations for how to use these other variants in warfarin dosing. An alternate name for rs9923231 is -1639G>A (note that VKORC1 is on the negative chromosomal strand, so displayed alleles are complemented).

For more information see the annotation on PharmGKB.

Citations:

Guideline annotation last modified: 2017.02.08

Allele Matching Details

  1. CFTR allele match data
  2. CYP2C19 allele match data
  3. CYP2C9 allele match data
  4. CYP2D6 allele match data
  5. CYP3A5 allele match data
  6. CYP4F2 allele match data
  7. DPYD allele match data
  8. IFNL3 allele match data
  9. SLCO1B1 allele match data
  10. TPMT allele match data
  11. UGT1A1 allele match data
  12. VKORC1 allele match data

CFTR allele match data

Genotype matched

Phasing status

Phased

Calls at Positions

Position RSID Call Reference Related Alleles
117509035 rs397508256 G|G G E56K
117509069 rs368505753 C|C C P67L
117509089 rs115545701 C|C C R74W
117509123 rs75961395 G|G G G85E
117530953 rs113993958 G|G G D110H
117530955 rs397508537 C|C C D110E
117530974 rs77834169 C|C C R117C
117530975 rs78655421 G|G G R117H
117531115 rs78756941 G|G G 621+1G->T
117534318 rs80282562 G|G G G178R
117534363 rs397508759 G|G G E193K
117534366 rs77188391 G|G G 711+1G->T
117535285 rs121908752 T|T T L206W
117540230 rs121909011 C|C C R334W
117540270 rs77932196 G|G G R347H R347P
117540285 rs121908753 G|G G R352Q
117548795 rs74551128 C|C C A455E
117559590 rs121908745 ATC|ATC ATC I507
117559592 rs113993960 CTT|CTT CTT F508del(CTT)
117587738 rs76713772 G|G G 1717-1G->A
117587778 rs113993959 G|G G G542X
117587799 rs121908757 A|A A S549R(A>C)
117587800 rs121908755 G|G G S549N
117587801 rs121909005 T|T T S549R(T>G)
117587805 rs121909013 G|G G G551S
117587806 rs75527207 G|G G G551D
117587811 rs74597325 C|C C R553X
117587833 rs80055610 G|G G R560T
117590409 rs397508288 A|A A D579G
117590440 rs121908748 G|G G 1898+1G->A
117592219 rs121908746 A|A A 2184delA
117602868 rs80224560 G|G G 2789+5G->A
117603708 rs397508442 C|C C S945L
117606695 rs141033578 C|C C S977F
117606754 rs75096551 G|G G 3120+1G->A
117611595 rs150212784 T|T T F1052V
117611620 rs397508513 A|A A K1060T
117611640 rs121909020 G|G G A1067T
117611646 rs200321110 G|G G G1069R
117611649 rs202179988 C|C C R1070W
117611650 rs78769542 G|G G R1070Q
117611663 rs186045772 T|T T F1074L
117614699 rs75541969 G|G G D1152H
117627537 rs74767530 C|C C R1162X
117627581 rs121908747 C|C C 3659delC
117639961 rs75039782 C|C C 3849+10kbC- >T
117642451 rs267606723 G|G G G1244E
117642472 rs74503330 G|G G S1251N
117642483 rs121909041 T|T T S1255P
117642528 rs11971167 G|G G D1270N
117642566 rs77010898 G|G G W1282X
117652877 rs80034486 C|C C N1303K
117664770 rs193922525 G|G G G1349D

CYP2C19 allele match data

Genotype matched

Phasing status

Phased

Calls at Positions

Position RSID Call Reference Related Alleles
94761665 rs7902257 G|G G *27
94761900 rs12248560 C|C C *4B *17
94762706 rs28399504 A|A A *4A *4B
94762712 rs367543002 C|C C *34
94762715 rs367543003 T|T T *34
94762755 rs55752064 T|T T *14
94762760 rs17882687 A|A A *15 *28
94762788 A|A A *29
94762856 A|A A *19
94775106 rs145328984 C|C C *30
94775121 C|C C *31
94775160 rs118203756 G|G G *23
94775185 A|A A *32
94775367 rs12769205 A|A A *2 *35
94775416 rs41291556 T|T T *8
94775453 rs72552267 G|G G *6
94775489 rs17884712 G|G G *9
94775507 rs58973490 G|G G *11
94780574 rs140278421 G|G G *22
94780579 rs370803989 G|G G *33
94780653 rs4986893 G|G G *3
94781858 rs6413438 C|C C *10
94781859 rs4244285 G|G G *2
94781944 G|G G *26
94781999 rs72558186 T|T T *7
94842861 rs138142612 G|G G *18
94842879 rs118203757 G|G G *24
94842995 rs113934938 G|G G *28
94849964 rs377184510 A|A A *24
94849995 rs17879685 C|C C *13
94852738 rs56337013 C|C C *5
94852765 rs192154563 C|C C *16
94852785 rs118203759 C|C C *25
94852914 rs55640102 A|A A *12

CYP2C9 allele match data

Genotype matched

Phasing status

Phased

Calls at Positions

Position RSID Call Reference Related Alleles
94938683 rs114071557 A|A A *36
94938737 rs67807361 C|C C *7
94938771 rs142240658 C|C C *21
94938803 A|A A *22
94938828 rs564813580 A|A A *37
94941897 rs371055887 G|G G *20
94941915 G|G G *23
94941958 rs72558187 T|T T *13
94941976 G|G G *38
94941982 rs762239445 G|G G *39
94942018 T|T T *40
94942213 AGAAATGGAA|AGAAATGGAA AGAAATGGAA *25
94942216 A|A A *41
94942230 rs767576260 C|C C *43
94942231 rs12414460 G|G G *42
94942234 rs72558189 G|G G *14 *35
94942249 rs200965026 C|C C *26 *44
94942254 rs199523631 C|C C *45
94942255 rs200183364 G|G G *33
94942290 rs1799853 C|C C *2 *35
94942305 rs754487195 G|G G *46
94942309 rs7900194 G|G G *8 *27
94947782 rs72558190 C|C C *15
94947785 rs774550549 C|C C *47
94947907 A|A A *57
94947917 T|T T *48
94947938 A|A A *28
94949129 A|A A *49
94949144 C|C C *50
94949217 rs2256871 A|A A *9
94949280 rs9332130 A|A A *10
94949282 rs9332131 A|A A *6
94972119 rs182132442 C|C C *29
94972134 A|A A *51
94972179 rs72558192 A|A A *16
94972180 C|C C *52
94972233 C|C C *53
94981201 rs57505750 T|T T *31
94981224 rs28371685 C|C C *11
94981225 rs367826293 G|G G *34
94981250 rs750820937 C|C C *54
94981281 rs749060448 G|G G *24
94981296 rs1057910 A|A A *3 *18
94981297 rs56165452 T|T T *4
94981301 rs28371686 C|C C *5
94981302 C|C C *55
94981365 C|C C *17
94986042 rs764211126 A|A A *56
94986073 rs72558193 A|A A *18
94988917 rs769942899 G|G G *19
94988984 rs781583846 G|G G *30
94989020 rs9332239 C|C C *12
94989023 G|G G *32

Other Positions of Interest

Position RSID Call
94645745 rs12777823 G/A

CYP2D6 allele match data

Genotype matched

Phasing status

Unavailable for Astrolabe calls
The call for CYP2D6 comes from Astrolabe data which does not supply position-level detail. For specific disclaimers and limitations, see Astrolabe specification.
No variant data available.
CYP2D6 genotypes are called by a separate algorithm from other genes in the PharmCAT report. Please refer to the PharmCAT wiki for more information.

CYP3A5 allele match data

Genotype matched

Phasing status

Phased
CYP3A5 is known to have one or more functional variants in intronic regions. Since intronic variants are important for CYP3A5 genotype assignment, further testing may be warranted for exome data.

Calls at Positions

Position RSID Call Reference Related Alleles
99652613 rs28365083 G|G G *2
99652770 rs41303343 del|del del *7
99660516 rs28383479 C|C C *3 *9
99665212 rs10264272 C|C C *6
99665237 rs56411402 T|T T *4
99666950 rs55965422 A|A A *5
99672916 rs776746 T|T T *3
99676198 rs55817950 G|G G *8

CYP4F2 allele match data

Genotype matched

Phasing status

Phased

Calls at Positions

Position RSID Call Reference Related Alleles
15879621 rs2108622 C|C C *3
15897578 rs3093105 A|A A *2

DPYD allele match data

Genotype matched

Phasing status

Phased

Calls at Positions

Position RSID Call Reference Related Alleles
97079071 rs1801268 C|C C c.2983G>T
97082391 rs67376798 T|T T c.2846A>T
97450058 rs3918290 C|C C c.1905+1G>A
97450066 rs72549303 G|G G c.1898delC
97515787 rs55886062 A|A A c.1679T>G
97573943 rs78060119 C|C C c.1156G>T
97579893 rs75017182 G|G G c.1129-5923C>G
97691776 rs1801266 G|G G c.703C>T
97699474 rs115232898 T|T T c.557A>G
97740415 rs72549309 AGTA|AGTA AGTA c.295_298delTCAT

Other Positions of Interest

These variants are included in the CPIC supplementary material for DPYD. Variants with 'In vitro data only and/or limited clinical/ex vivo data' evidence level are not specifically included in the CPIC recommendations. The table also lists normal function variants with different evidence levels based on the guideline information. For further details follow the link to the CPIC page in the fluorouracil or capecitabine drug section.
Position RSID Call
97078987 rs114096998 missing
97078993 rs148799944 missing
97079005 rs140114515 missing
97079076 rs139459586 missing
97079077 rs202144771 missing
97079121 rs72547601 missing
97079133 rs72547602 missing
97079139 rs145529148 missing
97082365 rs141044036 missing
97098598 rs1801267 missing
97098599 rs147545709 missing
97098616 rs55674432 missing
97098632 rs201035051 missing
97193109 rs60139309 missing
97193209 rs200687447 missing
97234958 rs199634007 missing
97234991 rs56005131 missing
97235033 rs12137711 missing
97305279 rs112766203 missing
97305363 rs60511679 missing
97305364 rs1801160 missing
97305372 rs146529561 missing
97306195 rs145548112 missing
97373598 rs137999090 missing
97373629 rs138545885 missing
97382461 rs55971861 missing
97450059 rs3918289 missing
97450068 rs17376848 missing
97450168 rs147601618 missing
97450187 rs145773863 missing
97450189 rs138616379 missing
97450190 rs59086055 missing
97515686 rs2811178 missing
97515687 rs2786783 missing
97515784 rs201615754 missing
97515839 rs1801159 missing
97515851 rs142619737 missing
97515865 rs1801158 missing
97515889 rs190951787 missing
97515923 rs148994843 missing
97549565 rs138391898 missing
97549600 rs111858276 missing
97549609 rs72549304 missing
97549681 rs199549923 missing
97549713 rs57918000 missing
97549726 rs144395748 missing
97549735 rs72975710 missing
97549850 rs61789183 missing
97573785 rs186169810 missing
97573805 rs142512579 missing
97573821 rs764666241 missing
97573839 rs200064537 missing
97573881 rs61622928 missing
97573918 rs143815742 missing
97573919 rs140602333 missing
97573985 rs56293913 missing
97573998 rs368600943 missing
97593238 rs72549305 missing
97593289 rs143154602 missing
97593322 rs183385770 missing
97593343 rs72549306 missing
97593379 rs201018345 missing
97594925 rs2811202 missing
97595083 rs145112791 missing
97595088 rs150437414 missing
97595149 rs146356975 missing
97679004 rs138924556 missing
97679054 rs112550271 missing
97679170 rs45589337 missing
97679300 rs3790387 missing
97691806 rs74774246 missing
97699212 rs6668296 missing
97699399 rs72549307 missing
97699430 rs72549308 missing
97699506 rs6670886 missing
97699533 rs139834141 missing
97699535 rs2297595 missing
97721542 rs200562975 missing
97721650 rs141462178 missing
97740400 rs150385342 missing
97740602 rs41309171 missing
97828265 rs115632870 missing
97883329 rs1801265 missing
97883352 rs80081766 missing
97883353 rs72549310 missing
97883368 rs150036960 missing

IFNL3 allele match data

Genotype matched

Phasing status

Phased

Calls at Positions

Position RSID Call Reference Related Alleles
39248147 rs12979860 C|C C rs12979860T

SLCO1B1 allele match data

Genotype matched

Phasing status

Phased

Calls at Positions

Position RSID Call Reference Related Alleles
21130388 rs4149015 G|G G *17 *21
21172734 rs139257324 C|C C *33
21172776 rs373327528 G|G G *23
21172782 rs56101265 T|T T *2 *12
21174595 rs56061388 T|T T *3 *13
21176804 rs2306283 A|A A *1B *14 *15 *17 *18 *20 *21 *24 *25 *27 *28 *29 *30 *31 *32 *33 *35
21176827 rs11045818 G|G G *18
21176868 rs2306282 A|A A *16
21176879 rs11045819 C|C C *4 *14 *18 *25 *32
21176883 rs72559745 A|A A *3 *13
21178615 rs4149056 T|T T *5 *15 *17
21178665 rs4149057 T|T T *18 *19
21178672 rs72559746 T|T T *18
21178691 rs2291075 C|C C *20 *21
21178957 rs79135870 A|A A *30
21196951 rs11045852 A|A A *24 *25 *28 *32 *33
21196976 rs11045853 G|G G *25 *28 *33
21200595 rs55901008 T|T T *6
21202553 T|T T *36
21202555 rs59113707 C|C C *27
21202649 rs56387224 A|A A *7
21202664 rs142965323 G|G G *26
21205921 rs72559748 A|A A *8
21205999 rs59502379 G|G G *9 *31
21239042 rs34671512 A|A A *19 *20 *22 *35
21239077 rs56199088 A|A A *10 *12
21239113 rs55737008 A|A A *11 *13
21239145 rs200995543 C|C C *34
21239158 rs140790673 C|C C *29

TPMT allele match data

Genotype matched

Phasing status

Phased

Calls at Positions

Position RSID Call Reference Related Alleles
18130687 rs1142345 T|T T *3A *3C
18130694 rs150900439 T|T T *20
18130725 rs72552736 A|A A *7
18130762 rs56161402 C|C C *8
18130772 rs377085266 A|A A *25
18130781 rs1800584 C|C C *4
18132136 rs72556347 A|A A *26
18132147 rs79901429 A|A A *31
18133845 rs75543815 T|T T *6
18133847 rs6921269 C|C C *24
18133884 rs74423290 G|G G *23
18133890 rs9333570 C|C C *15
18138969 rs144041067 C|C C *16 *22
18138997 rs1800460 C|C C *3A *3B
18139027 rs72552737 C|C C *10
18139689 rs72552738 C|C C *11
18139710 rs200220210 G|G G *12
18143597 T|T T *19
18143606 rs151149760 T|T T *9
18143613 C|C C *28
18143643 A|A A *27
18143724 rs1800462 C|C C *2
18147845 C|C C *18
18147851 rs200591577 G|G G *21
18147910 rs72552740 A|A A *5
18149004 G|G G *17
18149022 C|C C *30
18149045 rs72552742 T|T T *13
18149126 rs267607275 A|A A *29
18149127 rs9333569 T|T T *14

Other Positions of Interest

The following position is included in the CPIC TPMT allele defintions but not in the recommendation.
Position RSID Call
18138983 rs2842934 G|G

UGT1A1 allele match data

Genotype matched

Phasing status

Phased
UGT1A1*80 (rs887829) is in very high linkage disequilibrium with *28 and *37 (TA repeat variation in the UGT1A1 promoter). In case *80 (rs887829) is detected and input at position 233760233 (*28/*37) is MISSING from the VCF, the allele options are presented as *80+*28 and *80+*37 based on a partial match for *80, and *80 is used to infer metabolizer status.

In case *80 is detected with position 233760233 (*28/*37) detected as reference (shown as reference in row 233760233 in the table Calls at Position), not enough clinical data exists to predict metabolizer status with certainty and provide recommendations. Therefore, the presence of *80 (without the *28 or *37 variant) is not considered in the determination of the UGT1A1 genotype by itself.

Calls at Positions

Position RSID Call Reference Related Alleles
233757013 rs4124874 T|T T *60
233759924 rs887829 C|C C *80+*28 *80+*37
233760233 CAT|CAT CAT *28 *36 *37 *80+*28 *80+*37
233760498 rs4148323 G|G G *6
233760973 rs35350960 C|C C *27

VKORC1 allele match data

Genotype matched

Phasing status

Phased

Calls at Positions

Position RSID Call Reference Related Alleles
31096368 rs9923231 T|T C -1639A

Disclaimers and Other Information

Liability: PhamCAT assumes no responsibility for any injury to person or damage to persons or property arising out of, or related to any use of PharmCAT, or for any errors or omissions. The user recognizes that PharmCAT is a research tool and that they are using PharmCAT at their own risk.

A. Allele and Genotype Determination

  1. PharmCAT uses gene allele definitions from CPIC, with exceptions as noted in Gene Definition Exceptions document. For allele definitions and the positions used in PharmCAT, see the gene definition tables.
  2. PharmCAT results are dependent on the supplied vcf calls for the queried positions (for technical information about PharmCAT input formatting and requirements, please go to pharmcat.org). PharmCAT does not assume any reference calls for positions missing from the submitted vcf; all missing queried positions are not considered in the allele determination process. See the gene definition tables for more information about what positions are queried in the vcf. Missing positions might alter the assigned genotype, subsequent phenotype prediction and CPIC recommendation. If the supplied vcf is missing positions, those positions will be noted in Section 3: Allele Calls for each gene of this report. For the most reliable allele determination, reference calls as well as variant calls in the vcf for every queried position must be provided by the user.
  3. For cytochrome P450 genes, TPMT, DPYD, and SLCO1B1, the *1 (or reference in case of DPYD) allele is defined by the absence of variation specified in the gene definition tables. This allele cannot be identified by variants; rather, *1 is assigned by default when no variation for the queried positions is reported in the submitted vcf. It is always possible un-interrogated variation can occur which could potentially affect allele function, but because it is undetected, the assignment would be defaulted to a *1 allele and normal function.
  4. For all genes, variation reported in the vcf but NOT included in the gene definition table will not be considered during allele assignment. There is a possibility that any such variation results in a reduced or no activity allele which could lead to inaccurate phenotype and CPIC recommendation, similar to the situation in point iii, above.
  5. PharmCAT matches variants to genotypes using unphased data (unless phased data is provided in the vcf and noted as such, see pharmcat.org for details). The assumption is that defined alleles exist in trans configuration, i.e. on opposite chromosomes, with exceptions noted in Section 3: Allele Calls under “Gene-specific warnings.” However, in cases where an allele is defined by a combination of two or more variants, where each variant alone also defines an allele, the match is based on the longer allele (except for UGT1A1). For example, CYP2C19*4A is defined one SNP, *17 is defined by another SNP, and *4B is defined by the combination of those two SNPs. In the case of unphased data that is heterozygous for both SNPs, the *1/*4B genotype is returned though the possibility of *4A/*17 cannot be ruled out.
  6. Nucleotide base calls are displayed on the positive chromosomal strand regardless of the gene strand; further information is provided under Gene-specific warnings in Section 3: Allele Calls.

B. CPIC Allele Function, Phenotype and Recommendation

  1. Allele functionality and phenotype terms are based on the CPIC Term Standardization Project [PMID: 27441996]. Please see this reference for details but note the following changes from original CPIC guidelines based on this project:
    1. This terminology replaces the term ‘extensive’ metabolizer with ‘normal’ metabolizer for drug metabolizing enzymes such as CYPs, DPYD, TPMT, UGT1A1. Guidelines published prior to this recommendation used the term ‘extensive’ metabolizer whereas the PharmCAT report uses ‘normal’.
    2. The terminology introduces the use of the term ‘rapid’ metabolizer for CYP2C19*1/*17 to distinguish between *1/*17 and *17/*17 (‘ultrarapid’ metabolizer). CYP2C19 *1/*17 was grouped as ‘ultrarapid’ metabolizer in prior guidelines. PharmCAT uses the ‘rapid’ metabolizer group.
    3. PharmCAT uses allele functions from gene information tables, including alleles with ‘possible’ or ‘likely’ added to the function term.
  2. PharmCAT uses metabolizer phenotypes from gene information tables. ‘Likely’ or ‘possible’ metabolizer phenotypes are originally based on supplemental materials for respective guidelines and are listed in the gene “Diplotype-Phenotype Table.”
  3. PharmCAT uses recommendation wording as provided in the CPIC guideline. CPIC typically provides the same recommendations for ‘likely’ or ‘possible’ metabolizer phenotypes in supplemental and gene information tables as those without the ‘likely’ or ‘possible’ labels, but do not provide a strength of therapeutic recommendation.

C. CYP2D6 Allele Determination and Metabolizer Status

  1. CYP2D6 genotypes are based on Astrolabe calls. For specific disclaimers and limitations, see the Astrolabe documentation and specifications made available with the product.
  2. Metabolizer Status: CPIC classifies genotypes with a gene activity score of 1.0 as normal metabolizers; however, other guidelines or reference laboratories may classify the same genotypes as intermediate metabolizers.

D. Prescribing Change Designations

  1. The drugs in Section 1: Genotype summary table are colored to indicate whether CPIC recommends a prescribing change based on the given genotype; highlighting is not based on CPIC classification of recommendation.
    1. Red indicates a prescribing change is recommended for the given genotype. That is, the recommendation is different than ‘use label recommendation’ or ‘use recommended starting dose’, except for ivacaftor.
    2. Orange indicates possible prescribing changes depending on additional information, e.g. pediatrics vs. adult, or the specific number of CYP2D6 normal alleles present (copy number).
    3. Green indicates that there is no CPIC recommended prescribing change for the given genotype, except for ivacaftor.
    4. Blue indicates the specific guideline must be consulted because a CPIC recommended action cannot be provided based solely on genotype (eg. warfarin and ribavirin/peginterferon).
  2. When multiple genotypes are possible for a gene, the drug is highlighted according to the highest level of prescribing change.

E. PharmCAT Exceptions to the CPIC Guideline Gene List

  1. HLA-B and G6PD are currently not included in PharmCAT. Therefore, no CPIC guideline recommendations are included for these genes.
  2. Further genes will be incorporated into PharmCAT as the tool is developed.

F. PharmCAT Updates

  1. PharmCAT monitors publication of new CPIC guidelines and guideline updates. New publication content will be included into PharmCAT within one month of CPIC publication.
  2. Updates to the gene definition tables may occur, the latest version can be found alongside the software releases.
  3. Updates to PharmCAT may occur, for the latest version go to the PharmCAT release page.

G. CPIC Guideline Disclaimers and Caveats

  1. A version of the following quoted disclaimer is part of each CPIC guideline and applies to the CPIC recommendations as used in PharmCAT. For the full description of potential benefits and risks, additional considerations (general and specific to gene-drug pairs), limitations, information about respective gene nomenclature systems, potential drug-drug interactions and clinical factors to consider, please see individual CPIC guidelines (cpicpgx.org).
    1. “CPIC guidelines reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision making and to identify questions for further research. New evidence may have emerged since the time a guideline was submitted for publication. Guidelines are limited in scope and are not applicable to interventions or diseases not specifically identified. Guidelines do not account for all individual variations among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guidelines is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. CPIC assumes no responsibility for any injury to persons or damage to persons or property arising out of or related to any use of CPIC’s guidelines, or for any errors or omissions.” (PMID: 27997040)
    2. “Caveats: appropriate use and/or potential misuse of genetic tests. The application of genotype-based dosing is most appropriate when initiating therapy with a tricyclic. Obtaining a pharmacogenetic test after months of drug therapy may be less helpful in some instances, as the drug dose may have already been adjusted based on plasma concentrations, response, or side effects. Similar to all diagnostic tests, genetic tests are one of several pieces of clinical information that should be considered before initiating drug therapy.” (PMID: 27997040)
  2. CPIC guidelines reflect the alleles/genotypes known and considered by the guideline authors for inclusion by the time of publication, however they may be updated online at cpicpgx.org in between publications. Additional alleles and/or more extensive allele definitions might exist by the representative gene nomenclatures for various genes.
  3. CPIC is a registered service mark of the U.S. Department of Health & Human Services (HHS).

H. PharmGKB Disclaimers and Caveats

  1. PharmGKB is a registered service mark of the U.S. Department of Health & Human Services (HHS).