Monday, May 20, 2019

PharmVar core alleles to be used by PharmGKB and CPIC

PharmVar has released core alleles - single, rule-based definitions per star allele distilled from the respective suballeles - for the cytochrome P450 genes CYP2C9CYP2C19, and CYP2D6. Only sequence variations that change an amino acid or impact function by changing expression levels or interfere with splicing and are present in ALL suballeles within a star allele, are part of the core allele definition. Read more about the core alleles in the PharmVar STANDARDS document and in each gene's "READ ME" document. 

Furthermore, part of the latest PharmVar release was the reassignment of CYP2C19*27 to CYP2C19*1.006.

The PharmGKB/CPIC allele definition tables are updated to reflect the core alleles for CYP2C9, CYP2C19, and CYP2D6 and the CYP2C19*27 change.

The PharmGKB/CPIC allele definition files include a “core alleles + overlap” view which reflects the existence of variants in some, but not all, suballeles of a star allele (therefore not part of the core allele) which are also part of core alleles of other star alleles. 

See the following examples.

CYP2D6 100C>T (P34S) is part of some but not all CYP2D6*4 suballeles. Therefore, it is not present in the CYP2D6*4 core allele. However, 100 C>T is part of core allele definitions of a number of CYP2D6 star alleles such as CYP2D6*10.
To reflect the ambiguous presence of 100C>T in the *4 core allele, the variant is represented as a “R” using IUPAC nucleotide code. "R" reflects that either a “G” or “A” (positive strand) can be present at the 100C>T position in *4.

A similar example is 12802G>A (R150H) in CYP2C19. The variant is present in the CYP2C19*11 core allele but also in one of the CYP2C19*2 suballeles. Therefore, 12802G>A is represented as a “R” in the CYP2C19*2 core allele.

This overlap of variants between alleles is visualized in gray (G) in PharmVar’s Comparative Allele ViewEr (CAVE) tool (accessible through the ‘Compare View’ on the gene page), which was released on PharmVar together with the core alleles (see gene "READ ME" documents for more information).

No comments: