Structural Variation CYP2C19

CYP2C reference gene locus The CYP2C gene locus contains four genes, CYP2C8, CYP2C9, CYP2C18 and CYP2C19 (Figure 1) spanning a total of 486 kb. All four genes are composed of nine exons and share high degrees of sequence similarities. This document provides an overview of genetic variation affecting the CYP2C19 gene locus and detailed information regarding structural variants.

Figure 1

Variant CYP2C19 alleles Alleles with SNVs: The majority of CYP2C19 allelic variants carry one or more SNV (Figure 2). These alleles may have increased, normal, decreased or no function. All allelic variants with SNVs are defined in the PharmVar database.

Figure 2

Copy number variation (CNV) Numerous deletion and duplication events affecting the CYP2C gene locus have been described. A comprehensive summary is provided by (Botton et al (2019), Hum Mut (Appendix, PMID 31260137). Many of the gene deletion and duplication events involve more than one of the CYP2C genes and can even encompasses a large number of genes within this chromosomal region. The following sections detail the structural variants that were part of a PharmVar submission to obtain star allele designations for CYP2C19 CNVs (variants were also submitted to the LOVD database). We encourage other investigators to submit their structural variants to PharmVar for cataloging.

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Structural Variation CYP2C19

Deletions CYP2C19 whole gene deletions: Two allelic variants carried large deletions affecting CYP2C19 and two adjacent genes as illustrated in Figure 3. These structural variants represent nonfunctional CYP2C19 alleles and were collectively designated as CYP2C19*36 (Table 1).

Figure 3

Table 1 CYP2C19 Whole Gene Deletions allele Genes deleted references PMID designation *36.001 CYP2C19, CYP2C18, HELLS Botton et al 31260137

*36.002 CYP2C19, CYP2C18, HELLS, TBCID12 Botton et al 31260137

CYP2C19 partial gene deletions: A number of allelic variants with partial deletions of CYP2C19 were identified using genome-wide copy number microarrays and confirmed by quantitative gene copy number assays targeting specific CYP2C19 regions. These variants are believed to be the products of large deletions between CYP2C18 and CYP2C19. As shown in Figure 4 the number of remaining exons can vary in either gene. A common feature of all these structural variants is the lack of exon 1. Since this exon encodes amino acids that guide protein synthesis to the endoplasmic reticulum, these variants, collectively designated as CYP2C19*37, are most likely not encoding functional protein.

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Structural Variation CYP2C19

Figure 4 illustrates deletions involving exons on the 5’ end of CYP2C19 (exons 1-7) and the 3’end of CYP2C18 (exons 2-9).

Table 2 CYP2C19 Partial Gene Deletions. All variants lack at least exon 1 allele Genes Exons references PMID designation deleted *37.001 CYP2C18 none Botton et al 31260137 CYP2C19 1-5 CYP2C18 8-9 *37.002 Botton et al 31260137 CYP2C19 1-4 *37.003 CYP2C18 1-9 Botton et al 31260137 CYP2C19 1 *37.004 CYP2C18 5-9 Botton et al 31260137 CYP2C19 1-7 *37.005 CYP2C18 2-9 Botton et al 31260137 CYP2C19 1-7

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Structural Variation CYP2C19

References The references provided in this Structural Variation document include the citation in which an allele was first published and additional reference(s) describing important updates and/or information regarding function. The reference list is not intended to provide a complete bibliography for an allele. Users are encouraged to share their research with and/or bring important literature that might have inadvertently been missed to the attention of PharmVar.

Allele frequencies CYP2C19 allele frequency tables have been developed for CPIC guidelines and are available through the PharmGKB at https://www.pharmgkb.org/page/cyp2c19RefMaterials. A comprehensive list of frequencies and references can be found in the CYP2C19 allele frequency table in the ‘source’ tab. These tables are periodically updated. These tables do not contain, however, information regarding the frequencies of CYP2C19 gene deletions as these are not routinely tested and thus, information is still sparse. CYP2C19 deletions appear to be rare at frequencies of <0.023 (Botton et al (2019), Hum Mut (Appendix, PMID 31260137).

Changes and Edits Suballeles are designated using the revised nomenclature system that replaced letters (e.g. A, B, etc.) with .001, .002, etc.). A number of changes and edits have been made compared to the original allele annotations to standardize annotations across genes and correct errors. Please see the Change Log document for specific details.

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