Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting

Abstract

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Figure 1

Reference sequence and genotype calls for one representative variant of the ABCB1 gene (rs1045642). Genomic DNA was tested using NGS by five laboratories as part of a GeT-RM study. The result from one sample (HG00276) is shown. Reference indicates the rs1045642 sequence against which the test sample was called. As shown, the sample was heterozygous for rs1045642, but was reported as C/T when C was used as reference and A/G when A served as reference. The test result, i.e. the detection of heterozygosity, was accurately achieved by all five laboratories; however, the actual reporting against different reference sequences is difficult to interpret.

Figure 2

CYP2C19*2, *4, and *17 alleles are used to illustrate how metabolizer phenotypes will be miscalled if CYP2C19*2 and *17 but not CYP2C19*4, are tested. Four possible scenarios are shown (Cases A-D). Panel A shows the phenotypes based on testing the key SNVs for CYP2C19*2 and *17. Panel B shows the phenotypes based on testing the key variants for CYP2C19*2, *4 and *17. Phenotypes shown in red in Panel B would have been miscalled if rs28399504 is present in the sample, but not included in the assay. These alleles are used as example, demonstrating that all alleles affecting CYP2C19 functionality should be interrogated in order to accurately call phenotypes. (PM = poor metabolizer; IM = intermediate metabolizer; EM = extensive metabolizer; UM = ultrarapid metabolizer)

Figure 3

Example of a tool that can be used to convert between star allele and HGVS nomenclature for CYP2C19. Panel A. Portion of a haplotype - HGVS conversion table for CYP2C19. Coordinates from the Human Genome Reference Assembly [e.g. NC_000010.10 (GRCh37), NC_000010.11 (GRCh38)], RefSeqGene (NG_008384.2), reference transcript (NM_000769.2), and reference protein (NP_000760.1) are provided for each of the rs IDs indicated, as applicable. An LRG sequence is not currently available for this gene. The relative exonic location of each rsSNP is indicated. The haplotype status of each rsSNP is indicated as nonvariant (black font in the reference *1 haplotype) or variant (red font in the polymorphic haplotypes). The combination of variants that compose each haplotype is also shown. Cells with gold shading indicates the defining SNP for each haplotype. Cells with red shading indicates rsSNPs with more than one possible variant nucleotide. HGVS nomenclature was derived from the dbSNP rs ID using the Mutalyzer SNP Converter tool (https://www.mutalyzer.nl/). Panel B. Detail of CYP2C19 haplotype - HGVS conversion table showing variants defining CYP2C19*4, *4A and *4B haplotypes.