Clinical proteomics in variant classification: are we there yet?

Variants of uncertain significance (VUS) represent a major barrier to diagnosis in rare diseases. Functional evidence is critical for variant classification under ACMG/AMP guidelines, yet most functional tests lack scalability and standardisation, making them unsuitable for implementation in diagnostic labs. We developed an untargeted mass spectrometry-based proteomics pipeline that quantifies proteins encoded by >50% of mendelian disease genes in clinically relevant specimens, including fibroblasts, skeletal muscle, and peripheral blood mononuclear cells. 1