Daniel L. Holmes

Pathway-scale variant effect mapping reveals the importance of cell context

The paper measures variant effects across the MAPK pathway in human cells, revealing how cell context influences variant function and identifying 14,412 previously unknown dominant negative variants.

An integrated, scaled approach to resolve TSC2 variants of uncertain significance

Abundance scores for 8,891 TSC2 missense variants, plus mTOR pathway activity scores for 391, were calibrated to ACMG/AMP evidence. They putatively reclassify 212 of 276 clinical-cohort missense VUS.

Evidence for G6PD variant classification from multiplexed functional assays

The paper classifies G6PD variants using functional assays to identify clinically relevant variants and those unlikely to contribute to G6PD deficiency.

Image-based, pooled phenotyping reveals multidimensional, disease-specific variant effects

The paper introduces VIS-seq, an image-based method to assess variant effects on cellular phenotypes, revealing multidimensional variant impacts across different diseases.

A scalable approach to resolving variants of uncertain significance

The paper develops a scalable workflow to reclassify variants of uncertain significance using experimental and predictive evidence, resolving 75% of VUS in 40 genes.