Evidence for G6PD variant classification from multiplexed functional assays.

Multiplexed deep mutational scanning: two high-throughput functional assays (enzymatic activity + protein abundance) on 9,504 G6PD variants

G6PD deficiency is one of the most common enzyme deficiencies worldwide, with direct pharmacogenomic implications (reactions to oxidative drugs). High-throughput multiplexed functional assays measuring enzymatic activity and protein abundance were conducted on 9,504 G6PD variants, enabling reclassification of 4,773 VUS with robust functional data. This deep mutational scanning resource is fully available in open access. Combining the two assays improves concordance with existing clinical classification.

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Combining two independent functional assays reduces ambiguous cases and reinforces ACMG variant classification for G6PD — directly applicable in clinical PGx (contraindication with rasburicase, primaquine, dapsone). Large-scale deep mutational scanning is progressively establishing itself as the reference method for pharmacogenomic enzyme variants.

Clinical impact: 2/3 · Evidence strength: 3/3 · Novelty: 1/2 · Sample size: 1/1 · Publication status: 1/1 → Total: 8/10