Pharmacogenetic Report

The report presents the results of pharmacogenetic testing, which makes it possible to account for the patient's hereditary characteristics when prescribing medications. Genetic variants can affect the effectiveness and safety of therapy by increasing, reducing, or completely eliminating the response to treatment, or by raising the risk of adverse drug reactions.

Pharmacogenetic testing helps personalize the selection of medications and dosing regimens, minimize the risk of side effects, and improve the overall effectiveness of pharmacotherapy. This approach is especially important in the treatment of chronic and oncological diseases, where resistance to standard therapy is common.

Pharmacogenetic testing involves analyzing genetic variants in pharmacogenes. Pharmacogenes are genes encoding proteins involved in the pharmacokinetics and pharmacodynamics of medications. They include genes encoding drug-metabolizing enzymes; transporter proteins responsible for drug absorption, distribution, and elimination; and genes encoding drug targets.

Pharmacogene analysis was performed using the PharmCAT (Pharmacogenomics Clinical Annotation) tool. PharmCAT annotates SNVs/indels based on CPIC (Clinical Pharmacogenetics Implementation Consortium), PharmGKB (Pharmacogenomics Knowledge Base), DPWG (Dutch Pharmacogenetics Working Group), and the FDA (Food and Drug Administration).

caution

The pharmacogenetic report reflects expert consensus based on clinical data and peer-reviewed literature available at the time of publication and is intended solely to assist clinicians in the decision-making process. However, it does not account for all individual patient characteristics and cannot serve as the sole basis for prescribing or modifying therapy. The report is not a substitute for professional medical consultation, diagnosis, or treatment. The accuracy of the report largely depends on the quality of the source data.

The pharmacogenetic report consists of four sections: Identified Alleles, Diplotypes, Genotypes, and Disclaimer.

Identified Alleles#

The first section provides a brief summary of the pharmacogenetic report. It contains a summary table with the results of allele-level interpretation for pharmacogenetically significant genes. For a given gene, multiple detected alleles or haplotypes may be listed if the input data allow their unambiguous determination. All variants are grouped according to their functional impact - specifically, their effect on the activity of the encoded enzyme or transport protein.

Table columns:

Group - a functional category reflecting the impact of the detected alleles on protein activity. Possible groups:

Decreased Function - includes the following phenotypes:
- 0.0 (Poor Metabolizer), or Poor Metabolizer: little to no enzyme activity. Corresponds to combination of no function alleles and/or decreased function alleles in genes, encoding drug-metabolizing enzymes: CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, DPYD, NUDT15, TPMT, UGT1A1.
- Likely Poor Metabolizer. It can be determined for the CYP2C19 gene, encoding a member of the cytochrome P450 superfamily of enzymes, which is involved in drug metabolism.
- 1.0 (Intermediate Metabolizer), 1.5 (Intermediate Metabolizer), or Intermediate Metabolizer: decreased enzyme activity (activity between normal and poor metabolizer). Corresponds to combinations of normal function, decreased function, and/or no function alleles in genes, encoding drug-metabolizing enzymes: CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, DPYD, NUDT15, TPMT, UGT1A1.
  1.0 and 1.5 are activity scores used by PharmCAT. The enzyme activity with a score of 1.0 is closer to the lower limit of normal, while the enzyme activity with a score of 1.5 is slightly higher and closer to a normal metabolizer.
- Likely Intermediate Metabolizer. It can be determined for the CYP2C19 gene, encoding a member of the cytochrome P450 superfamily of enzymes, which is involved in drug metabolism.
- Possible Intermediate Metabolizer. It can be determined for the genes, encoding drug-metabolizing enzymes: CYP3A5, NUDT15 и TPMT.
- Poor Function: little to no transporter function. Corresponds to combination of no function alleles and/or decreased function alleles in genes, encoding transporters: ABCG2 and SLCO1B1.
- Decreased Function: decreased transporter function (function between normal and poor function). Corresponds to combinations of normal function, decreased function, and/or no function alleles in genes, encoding transporters: ABCG2 and SLCO1B1.
- Possible Decreased Function. It can be determined for the SLCO1B1 gene, encoding organic anion transporting polypeptide 1B1 (OATP1B1), which is involved in drug transportation.
- Deficient: deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD), encoded by the G6PD gene.
- Deficient with CNSHA: deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD), encoded by the G6PD gene, in chronic nonspherocytic hemolytic anemia (CNSHA).
Increased Function - includes the following phenotypes:
- Rapid Metabolizer: increased enzyme activity compared to normal metabolizers but less than ultrarapid metabolizers. Corresponds to combinations of normal function and increased function alleles in genes, encoding drug-metabolizing enzymes: CYP2B6 and CYP2C19.
- Ultrarapid Metabolizer: increased enzyme activity compared to rapid metabolizers. Corresponds to two increased function alleles, or more than 2 normal function alleles in genes, encoding drug-metabolizing enzymes: CYP2B6 and CYP2C19.
- Increased Function: increased transporter function compared to normal function. Corresponds to one or more increased function alleles in the SLCO1B1 gene, encoding organic anion transporting polypeptide 1B1 (OATP1B1), which is involved in drug transportation.
Side Effects: corresponds to the Malignant Hyperthermia Susceptibility phenotype, a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. It develops with mutations in the RYR1 and CACNA1S genes.
Drug Response - includes the following phenotypes:
- The "-1639 AA", "-1639 AG", "-1639 GG" genotypes of the VKORC1 gene, encoding drug-metabolizing enzyme. These variants differ in their levels of enzyme expression and, therefore, require different drug dosages. For example, patients with the -1639 AA genotype should be given 60% of the standard initial dose of warfarin, while there are no recommendation for patients with the -1639 AG genotype¹.
- ivacaftor non-responsive in CF patients: no response to ivacaftor treatment in patients with cystic fibrosis (CF). This phenotype corresponds to a situation where all analyzed variants in the CFTR gene are homozygous for the reference allele. Since the efficacy of ivacaftor has only been established in patients carrying certain genetic variants in the CFTR gene (either homozygous or heterozygous), the absence of such variants indicates a low probability of therapeutic response².
- ivacaftor responsive in CF patients: a probable positive response to ivacaftor treatment in patients with cystic fibrosis (CF). The phenotype is consistent with the detection of a genetic variant in the CFTR gene that is likely to be effective with ivacaftor. The presence of this mutation means the patient has a high chance of a positive response to therapy.
Normal Function - includes the following phenotypes:
- 2.0 (Normal Metabolizer), and Normal Metabolizer: fully functional enzyme activity. Corresponds to combinations of normal function and decreased function alleles in genes, encoding drug-metabolizing enzymes: CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, DPYD, NUDT15, TPMT, UGT1A1.
- Normal Function: fully functional transporter function. Corresponds to combinations of normal function and/or decreased function alleles in genes, encoding transporters: ABCG2 and SLCO1B1.
- Normal: normal activity of the enzyme glucose-6-phosphate dehydrogenase (G6PD), encoded by the G6PD gene. Corresponds to homozygote for the reference allele - B (reference)/B (reference).
Uncertain Effect - includes the following phenotypes:
- Indeterminate: a standardized CPIC phenotype term assigned to genotypes containing uncertain function or unknown function alleles. It can be determined for the following genes: CYP2B6, CYP2C19, CYP2C9, CYP3A5, G6PD, NUDT15, SLCO1B1, TPMT, UGT1A1.
- Uncertain Susceptibility: undefined susceptibility to malignant hyperthermia, a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Malignant hyperthermia susceptibility develops with mutations in the RYR1 and CACNA1S genes.
- Variable: variable activity of the enzyme glucose-6-phosphate dehydrogenase (G6PD), encoded by the G6PD gene.
- 0.5 (Phenotyping), 1.0 (Phenotyping), or Phenotyping: enzyme activity must be assessed using phenotyping. 0.5 and 1.0 are activity scores used by PharmCAT.
Conflicting Phenotypes: a category of results that arises when, for the same gene, different combinations of detected alleles or interpretations from different sources lead to incompatible phenotype assignments. In such cases, the patient's genotype cannot be reliably associated with a single, definitive phenotype.

Gene - the name of the analyzed gene. The analysis includes 18 pharmacogenetically significant genes:

ABCG2 and SLCO1B1 - genes encoding transporters;
CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, CYP4F2, DPYD, G6PD, NUDT15, TPMT, UGT1A1, and VKORC1 - genes encoding drug-metabolizing enzymes;
CACNA1S and RYR1 - genes associated with susceptibility to malignant hyperthermia;
CFTR - a gene that determines response to treatment with ivacaftor;
IFNL3 - a gene encoding cytokines, which are distantly related to type I interferons and the IL-10 family.

Alleles - pharmacogenetically relevant alleles (diplotypes) detected in the patient for the given gene. If there is ambiguity in allele assignment for a gene, all possible allele combinations are listed, separated by commas.
If no allele can be determined for a gene, the value "insufficient data to determine alleles" is reported. Such genes are then excluded from subsequent sections of the report.
Genetic variants identifiable as pharmacogenomic markers are described the star-allele nomenclature. In this nomenclature, alleles are not identified by their genomic position or HGVS notation, but are assigned labels such as *1, *2, *3, and so on. Each label corresponds to a specific genetic variant within the gene and its established functional effect. The use of star-allele nomenclature helps non-specialized professionals quickly and reliably identify clinically relevant pharmacogenetic alleles and reduces the risk of transcription mistakes which may be more frequent by using the standard HGVS nomenclature.
"Reference" or "*1" alleles are assigned by default when no alternative variants are found at the genetic positions relevant to determining pharmacogenetic alleles. Importantly, they do not suggest a lack of genetic variation at every position in the gene and should not be mistaken to mean an exact match to the entire reference sequence for the gene.
For the CFTR gene, the "Reference" designation corresponds to a CFTR variant that does not respond to ivacaftor therapy.

Diplotypes#

The "Diplotypes" section contains the results of pharmacogenetic data interpretation performed using the PharmCAT tool. The table includes only those genes for which the available input data were sufficient to determine a diplotype. For each identified diplotype, the table provides information on the functional impact of the corresponding alleles, the expected phenotype, and the drugs associated with the gene.

Table columns:

Gene - the name of the gene in which the relevant alleles were identified. For some genes, warnings are provided in footnotes below the table:

For CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP4F2, G6PD, NUDT15, SLCO1B1, TPMT, and UGT1A1, it is not always possible to unambiguously determine the diplotype when unphased genomic data are used. In such cases, diplotypes that determine the priority according to PharmCAT are indicated.
When no alternative nucleotides are detected in positions that determine pharmacogenomic alleles, the gene is assigned a reference allele ("Reference" or "*1"). Importantly, this does not suggest a lack of genetic variation at every position in the gene and should not be mistaken to mean an exact match to the entire reference sequence for the gene.
If at least one position in a gene lacks genotype information (i.e., the patient's variant nucleotides could not be determined), a footnote is added: "Diplotype predicted based on incomplete genomic data".

Diplotype - a combination of two haplotypes of a gene's alleles, inherited from each parent. It represents a pharmacogenetically relevant form of the patient's genotype. Diplotypes are translated by PharmCAT into the corresponding phenotypes. If diplotype assignment is ambiguous for a gene, all possible diplotypes are listed on separate rows.
Allele Functionality - a description of the clinical functional impact of the detected alleles on the activity of the encoded protein.
Phenotype - the interpretation of the diplotype from a pharmacogenetic perspective. It defines the patient's expected ability to metabolize specific drugs. Definitions of possible phenotypes are given above.
Drugs - a list of medications associated with the gene and for which the gene has clinical relevance. The list is based on CPIC and DPWG guidelines.

The primary source of information on diplotypes, allele functionality, and phenotypes is the Clinical Pharmacogenetics Implementation Consortium (CPIC). Information from CPIC is provided without special notation. If the Dutch Pharmacogenetics Working Group (DPWG) provides recommendations that differ from those of CPIC, they are indicated with the label "DPWG". In the example below for the VKORC1 gene, no CPIC recommendations were found for the identified diplotype, while DPWG provides information on drug response:

Genotypes#

The "Genotypes" section contains the genotyping results generated by PharmCAT and provides detailed information about the nucleotides present at the analyzed positions in the patient's genomic data. The section includes a list of 18 pharmacogenes; for each gene, the detected pharmacogenetically relevant variants are presented in the format "chromosome: position - genotype". For some genes, warnings and comments generated by PharmCAT are also displayed.

If nucleotide information is missing for certain positions, those positions are listed in the "Position data not provided" subsection in the format "chromosome: position".

Disclaimer#

PharmCAT uses gene allele definitions included in the CPIC database, with modifications for the CYP3A4, DPYD, G6PD, SLCO1B1, RYR1 genes. Exceptions are noted in Gene Definition Exceptions document.

CPIC assigns function terms to alleles based on literature evidence reviewed by a panel of experts in pharmacogenomics. CPIC aims to assign an allele function that leads to a phenotype assignment that can drive clinical prescribing actionability. It is important to note that an allele's CPIC-assigned function can differ from the biochemical function reported in the literature. For example, an allele may show a decrease in function under experimental conditions, but this decrease is so small that no change in prescribing action is required. As a result, this allele may be classified by CPIC as a normal function allele. CPIC prioritizes clinical interpretation over purely biochemical data. Therefore, CPIC function terms should always be considered in the context of clinical applicability.

The CYP3A4 gene is currently not part of a CPIC guideline. Since the DPWG CYP3A4 documentation includes limit variant notations for the included alleles (only *16, *20, and *22 are specified), PharmCAT relies on PharmVar CYP3A4 allele definitions. However, the CYP3A4*16, *20 and *22 definitions are the same in both sources.

PharmCAT does not replace missing genomic positions in the source data with reference variants; all missing positions are not considered when determining alleles. The absence of genomic position information in the source data may affect the prediction of alleles, diplotype, and phenotype. If an allele is determined by multiple genomic variants, but only some of them are present in the source data, PharmCAT will attempt to make a prediction based on the available information. This may result in several possible diplotypes with equally high priority. Additionally, alternative diplotypes with lower priority may be present.

Genomic positions display nucleotides from the positive strand of the chromosome regardless of gene orientation.

PharmCAT matches genomic variants with alleles and diplotypes, assuming the data is unphased unless phasing is explicitly specified in the source genomic data. By default, it is assumed that the determined alleles are in trans configuration, meaning on opposite chromosomes. However, in cases where an allele is determined by a combination of two or more variants, and each of these variants can also independently determine an allele, the "longer" allele determined by a larger number of variants will be output as the result.

There are cases where it is impossible to unambiguously differentiate between phased and unphased diplotypes. In such cases, diplotypes have different priorities according to PharmCAT. The diplotype with higher priority (the "longer" allele) will be used to determine the phenotype. However, the diplotype with lower priority is also possible. For the genes listed below, the diplotypes shown in unphased data are indistinguishable from the diplotypes shown in square brackets:

Gene CYP2B6: *1/*36 [*6/*22]; *1/*34 [*33/*36]; *1/*6 [*4/*9]; *1/*7 [*5/*6]; *1/*13 [*6/*8]; *1/*18 [*4/*18];
Gene CYP2C19: *1/*4 [*17/*4]; *1/*2 [*11/*2]; *1/*35 [*15/*35];
Gene CYP2C9: *1/*71 [*10/*22];
Gene CYP3A4: *1/*37 [*3/*22]; *1/*38 [*3/*11];
Gene CYP4F2: *1/*4 [*2/*3];
Gene G6PD: A- 202A_376G/B (reference) [A/Asahi]; B (reference)/Mt Sinai [A/Guadalajara]; B (reference)/Santa Maria [A/Malaga]; Ananindeua/B (reference) [A/Viangchan, Jammu]; B (reference)/Hechi [Asahi/Viangchan, Jammu]; B (reference)/Hermoupolis [Cassano/Union,Maewo, Chinese-2, Kalo];
Gene NUDT15: *1/*2 [*3/*6];
Gene SLCO1B1: *1/*46 [*15/*45]; *1/*20 [*19/*37]; *1/*12 [*2/*10]; *1/*13 [*3/*11]; *1/*14 [*4/*37]; *1/*15 [*5/*37]; *1/*25 [*4/*28]; *1/*31 [*9/*37]; *1/*32 [*4/*24]; *1/*40 [*5/*19]; *1/*43 [*4/*44];
Gene TPMT: *1/*3A [*3B/*3C];
Gene UGT1A1: *1/*80+*28 [*28/*80]; *1/*80+*37 [*37/*80].

See cases for which there is an overlap in the allele definitions in the PharmCAT documentation.

Report export#

The pharmacogenetic report can be downloaded in PDF format. To do this, click on the button in the upper right corner of the report page.