CYP2C19 c.681G>A Is not in Complete Linkage Disequilibrium With c.332-23A>G: Implications for Pharmacogenetic Testing

The no-function CYP2C19 2 allele, previously defined by three variants, is redefined by the single splice variant c.681G>A following the discovery of haplotypes lacking c.332-23A>G.

CYP2C19 metabolizes many drugs, including clopidogrel, voriconazole, selective serotonin reuptake inhibitors, selected tricyclic antidepressants and proton pump inhibitors, and is covered by several CPIC genotype-guided prescribing guidelines. The no-function CYP2C19 2 allele was defined by three variants — c.332-23A>G and c.681G>A, both splice defects, and c.991A>G (p.I331V) — until the discovery of two haplotypes, one carrying only c.681G>A and the other c.681G>A plus c.991A>G. PharmVar designated them CYP2C19 2.018 and 2.019, prompting revision of the CYP2C19 2 core allele to be defined solely by c.681G>A. The practical consequence is that a subject heterozygous both for c.332-23A>G, present on most CYP2C19 2 and all CYP2C19 35 alleles, and for c.681G>A, present on all CYP2C19 2 alleles, may in rare cases carry a poor metabolizer CYP2C19 2/35 diplotype with variants in trans rather than an intermediate metabolizer CYP2C19 1/2 diplotype with variants in cis. Alleles carrying c.681G>A without c.332-23A>G were found across diverse populations, with an estimated frequency around 0.03 %.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The frequency is low but the error it produces is not: calling a true poor metabolizer an intermediate metabolizer means keeping clopidogrel in someone who should be switched. The point to check in one's own laboratory is very concrete: most assays interrogate the right positions, but their reporting algorithm presupposes a cis configuration, and without phasing a double heterozygote remains ambiguous. It is a reminder that the value of a pharmacogenetic test rests as much on the diplotype-to-phenotype translation logic as on the list of variants tested.

Analysis by Dr Thibaut Benquey