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

CYP2C19 plays an important role in the metabolism of many medications, including the antiplatelet agent clopidogrel, the antifungal agent voriconazole, selective serotonin reuptake inhibitors, select tricyclic antidepressants, and proton pump inhibitors. The Clinical Pharmacogenetics Implementation Consortium has published several guidelines emphasizing the importance of CYP2C19 genotype-guided therapy to optimize patient outcomes. Formerly, the no function CYP2C19*2 allele was defined by three variants, c.332-23A>G (splice defect), c.681G>A (splice defect), and c.991A>G (p.I331V). The discovery of two new haplotypes, one containing only a single variant, c.681G>A, and another with only c.681G>A and c.991A>G, challenged the assumption that c.681G>A always occurred together with c.332-23A>G. PharmVar designated these new haplotypes as CYP2C19*2.018 and *2.019, respectively, prompting the revision of the CYP2C19*2 core allele to be defined solely by the single variant, c.681G>A. Although the variants interrogated to identify CYP2C19*2 and *35 remain the same, subjects who are heterozygous for c.332-23A>G (present on most CYP2C19*2 and all *35 alleles) and c.681G>A (present on all CYP2C19*2 alleles) may, in rare cases, have a CYP2C19*2/*35 poor metabolizer diplotype (variants in trans) and not a CYP2C19*1/*2 intermediate metabolizer diplotype (variants in cis). CYP2C19*2 alleles with c.681G>A, but not c.332-23A>G, were found in subjects across diverse populations and are estimated to have a frequency around 0.03%. These findings, along with the revision of the CYP2C19*2 core allele definition, have implications for variant testing, test interpretation and reporting.