Assistant Research Professor Indiana University Indianapolis, Indiana, United States
Background: Implementation of the recently updated G6PD CPIC guidelines for medication use in individuals with G6PD deficiency requires knowledge of variant function. G6PD is on the X chromosome, and one of the more common variants c.376A>G (“A+”) has been associated with G6PD activities ranging from 27% to normal. This variant has conflicting interpretations of pathogenicity on ClinVar, necessitating further investigation to form a consensus. Therefore, the objective of this study was to evaluate the G6PD activity of c.376A>G in the All of Us data. Methods: G6PD variants were extracted from All of Us whole genome sequencing VCF files for 472 participants with G6PD activity data. G6PD percent activity was calculated as the measured activity value divided by the average of the provided normal range or the median of all values of the same measurement type. Activity values were log2 transformed and each participant’s lowest value was used. Results: We identified the c.376A>G variant in 76 individuals, 44 of whom did not have other known pathogenic variants. Of those 44, homozygotes/hemizygotes of c.376A>G had a median activity of 100% (mean 105%), matching heterozygotes (median 100%, mean 103%) and participants without any pathogenic variants (median 100%, mean 99%). These comparisons were powered to detect a difference of at least 12% by T-tests, yet no differences were found (p>0.38). Homozygotes/hemizygotes for the known pathogenic c.202G>A (“A-”), were highly associated with decreased G6PD activity (29% of normal, p=6 x 10-5). Other known pathogenic variants (c.844G>C, c.1048G>C, and c.968T>C) were present in different combinations but had insufficient sample sizes to detect differences in activity. Conclusion: In the absence of other reduced function variants, the c.376A>G variant is unlikely to confer reduced G6PD activity.
.jpg "Nicholas Powell, PharmD photo")