The Pharmacogenomic Clinical Annotation Tool

View the Project on GitHub PharmGKB/PharmCAT

Gene Definition Exceptions

The genotype determination is based on CPIC gene definition tables, with the following modifications:

  1. CYP3A5
    1. Includes the a ‘Y’ at position rs28383479 to reflect the statement ‘Existence of the CYP3A5*3 polymorphism 6986A>G on the same allele cannot be excluded’ from the Pharmacogene Variation Consortium. The inclusion of the ambiguous nucleotide ‘Y’ in the *3 definition results in a *1/*3 genotype call in case rs28383479 C>T is present together with rs776746 T>C since the match is based on the longer allele.
  2. CYP2C9
    1. rs1057911 (G475=) has been removed from the CYP2C9*3 and 18 definition. In the supporting article cited for the CYP2C9*18 allele definition (PMID: 15371982, this synonymous variant is described in linkage with rs1057910, the defining variant for *3. However, the rs1057911 (G475=) variant seems to be present in further alleles beside *3 and *18.
  3. CYP2C19
    1. rs17885098 (99C>T) and rs3758581 (80161A>G, I331V) are not included in the PharmCAT allele definition table given the presence of these variants in almost all star alleles, including sub alleles of *1.
    2. rs4917623 (87106T>C) is an intronic variant in *18 and *19. Based on Table 3 of the reference (PMID: 16141610) for both alleles in the Pharmacogene Variation Consortium, the variant exists in other star alleles besides *18 and *19. Therefore, this intronic variant is not included in the PharmCAT allele definition table.
    3. Sequence information in the CYP2C19 5 prime region was not consistently included in the star allele definitions (see archived CYP2C19 version on the Pharmacogene Variation Consortium website). Five prime variations are included in the PharmCAT allele definition table if currently linked to functional relevance (-806C>T, *17). CYP2C19*27 was removed since the allele was reassigned to CYP2C19*1.006 (PharmVar release 4.0.1)
    4. The variant 12802G>A (R150H) is the defining variant of the *11 allele but can also exist on the *2 background (see PharmVar CYP2C19*2.010). To account for this possibility an ‘R’ at position 12802G>A (R150H) is included in the *2 definition.
  4. SLCO1B1
    1. CPIC provides recommendations based on the rs4149056 genotype or the SLCO1B1 star allele genotype as reporting options in Table 1 of the SLCO1B1/simvastatin guideline [PMID: 24918167]. While PharmCAT attempts to determine the star allele genotype for SLCO1B1, in case no call can be determined it provides the CPIC recommendation based on the rs4149056 variant genotype.
  5. UGT1A1
    1. Phased data: The CPIC recommendations are provided using the subject’s phased UGT1A1 genotype.
    2. Unphased data: All variant alleles found are listed, based on the vcf input and the UGT1A1 definition table. The CPIC recommendations are provided based on an exception logic.
    3. The allele definition table does not include a row for only *80 since the presence of the rs887829 variant without the detection of *28 or *37 is assigned uncertain function and there are not enough clinical data to predict metabolizer status with certainty. In the UGT1A1 gene section rs887829 is noted.
  6. CFTR
    1. In the CPIC CFTR allele definition table the F508del variation is represented as F508del(CTT) rs113993960 and F508del(TCT) rs199826652.
  7. TPMT
    1. *1S variant can be observed in combination with other TPMT variants on the same strand which confounds star allele calling. To reduce TPMT ‘no calls’ in PharmCAT the TPMT genotype is determined without considering the *1S allele. However, the variant (rs2842934) is provided in the TPMT gene section.
  8. DPYD
    1. HGVS variant names are used to connect recommendation to DPYD variation in the 2017 CPIC guideline update for DPYD and fluoropyrimidines.
    2. The PharmCAT DPYD gene definition table includes decreased and no function variants with strong and moderate evidence, see Allele Functionality Table. If none of these variants are detected in the VCF, recommendations are provided based on two functional alleles.
    3. The 2017 CPIC DPYD guideline update includes normal function variants with strong, moderate or weak evidence. These variants are not included in the PharmCAT allele definition table. However, these variants are listed in the DPYD gene section of the PharmCAT report.
    4. The CPIC DPYD Allele Functionality Table includes further no and decreased function variants with in-vitro data only 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, however, a list of these variants is provided in the DPYD gene section under “Other Positions of Interest”.