Monday, May 10, 2021

CPIC seeks feedback for MT-RNR1 terminology

We announced last December that the Clinical Pharmacogenetics Implementation Consortium (CPIC)  was launching its Term Standardization Pharmacogenetic Test Results - Part 2 project.  The project is currently focused on MT-RNR1, as that guideline wraps up.  

The MT-RNR1 Gene/Disease and PGx expert panels have agreed on terminology for MT-RNR1 and aminoglycoside-induced hearing loss for allele clinical function and phenotype.  The final terms are posted for review on the CPIC website.  Please send any feedback to Dr. Kelly Caudle at by May 28th, 2021.

Thursday, May 6, 2021

Rollout of genotype picker tool on DPWG guideline annotations

The allele pull-down menu (also known as the genotype-picker tool) on PharmGKB annotations of CPIC guidelines is an extremely popular feature among users. We are pleased to now expand this functionality to annotations of guidelines from the Royal Dutch Association for the Advancement of Pharmacy - Pharmacogenetics Working Group (DPWG).

The genotype picker tool relies on determining the following information from each guideline:

1. Which alleles are covered by the guideline

2. The assigned functional status of each allele

3. How allele function combinations are mapped to phenotype groups

The DPWG recommendations that are downloadable from the Dutch Pharmacy Organization’s (KNMP) website and annotated on PharmGKB do not typically contain allele functional status or phenotype group mappings. However, this information is often available in KNMP’s ‘gene background’ files which are posted separately.  While DPWG generally follows the same allele-to-phenotype mappings as CPIC, there are some gene-specific differences. These differences mean that all DPWG gene mappings need to be curated into PharmGKB separately from CPIC’s mappings. Our mapping process for each gene covered by DPWG guidelines, including curator notes, can be found here. As we now have internally curated mappings of allele function to phenotype for DPWG, more DPWG guidelines can now be used to support our Level 1A clinical annotations.

Genotype pickers are now available for all annotations of DPWG guidelines with recommendations for HLA-B, CYP2D6 and CYP2C19 genotypes. Work is ongoing to curate DPWG-assigned allele functions and phenotype groups for other genes into PharmGKB. As each gene is curated, genotype pickers will be released on relevant guideline annotation pages.

Tuesday, May 4, 2021

CYP3A4 now available in PharmVar

PharmVar and PharmGKB are excited to announce that CYP3A4 has been transitioned into the PharmVar database. Check it out here.

Numerous changes and revisions have been made during an extensive curation process including limiting the upstream and downstream regions used for allele definitions and the removal of introns of unknown functional consequence; these revisions caused the retirement of several suballeles or merging of suballeles.

In addition, upgrading to the gene’s current reference sequence (NG_008421.1) caused the c.-392A>G SNP to flip to c.-392G>A; in other words, all alleles that previously had the c.-392A>G SNP now match the RefSeq and are thus no longer showing the variant, while all other alleles gained c.-392G>A. Furthermore, the submission of new data added one novel star allele,CYP3A4*35, several novel suballeles, as well as helped to raise the evidence levels for many alleles from ‘Lim’ to ‘Def’.

Important CYP3A4 information is provided in the ‘Read Me’ document such as reference sequences used and how the PharmVar CAVE tool facilitates comparisons of core allele definitions. All changes and revisions have been summarized in the ‘Change Log’ document. Here we also provide a record of novel haplotypes that have been submitted to PharmVar and have been accepted. 

Finally, a big thank you to all CYP3A4 gene experts for volunteering their time and expertise!