Delivered the most comprehensive, reference-cited GLA variant database available, enabling FDA submission of therapy-eligible variants previously limited to EMA approval.
Produced variant classification and functional data packages aligned to FDA evidentiary standards, reducing back-and-forth and accelerating approval timelines.
Applied a novel enzyme activity threshold to reclassify 71 VUS to pathogenic, increasing patient eligibility and ensuring consistent variant interpretation across labs and regulators.
Amicus Therapeutics, the developer of Galafold for Fabry disease, faced a critical challenge — the therapy’s label in the US listed fewer GLA variants than the EMA label, limiting patient access. To expand the FDA label, Amicus needed to submit conclusive, reference-supported evidence for each variant’s pathogenicity.
Existing public resources like ClinVar were incomplete, with inconsistent classifications and missing functional data. Many therapy-eligible variants were listed as Variants of Uncertain Significance (VUS) or lacked the functional evidence required for FDA consideration. Without a comprehensive and defensible evidence set, label expansion could be delayed by years, restricting access for eligible patients and slowing market growth.
Genomenon partnered with Amicus to perform the most exhaustive GLA variant literature review to date, curating and classifying 1,677 unique variants from 1,634 publications.
Variant Landscape: The resulting GLA Variant Landscape integrated clinical, functional, and population frequency data, applying ACMG/AMP criteria to deliver classifications for every published variant. More than 800 variants identified in this review were not previously aggregated in any public database, with 512 classified as pathogenic/likely pathogenic.
Novel Enzyme Activity Threshold: Using functional assay results from FDA-approved variants as positive controls, Genomenon established evidence-based thresholds — <5.5% in vitro and <3.0% in vivo — for applying the ACMG PS3 functional criterion. Applying these thresholds promoted 71 VUS variants to pathogenic, directly increasing the pool of variants eligible for inclusion on the Galafold label.
Genetic Disease Sponsorship: The curated variant dataset was integrated into Mastermind and submitted to ClinVar, doubling the number of pathogenic/likely pathogenic GLA variants publicly available and ensuring lasting impact beyond the label expansion process.
Depth and Speed: Reduced a multi-year internal evidence-gathering process to weeks, enabling rapid regulatory action.
Evidence-Based Innovation: Introduced a scientifically justified enzyme activity threshold, replacing an arbitrary 3% cutoff and aligning classification with functional reality.
Regulatory Readiness: Delivered data in FDA compatible formats with full reference traceability, minimizing rework and accelerating the review process.
Global Impact: Supported alignment of FDA and EMA variant lists, ensuring that eligible patients in all jurisdictions could benefit from Galafold.
Expanded US label eligibility: Promoted 71 VUS variants to pathogenic using an evidence-based PS3 threshold, enabling FDA consideration for label inclusion.
Doubled public knowledge base: Submitted over 1,000 pathogenic/likely pathogenic variants to ClinVar, increasing transparency and supporting global diagnostic consistency.
Accelerated regulatory timelines: Delivered FDA-ready variant reports with complete functional and clinical evidence, reducing review cycles.
Improved patient access: Enabled more patients with Fabry disease to be eligible for Galafold in the US, matching broader EMA coverage.
Sustained diagnostic impact: Integrated curated GLA data into Mastermind for continuous public and clinical access, ensuring long-term utility for labs, clinicians, and researchers.
We help provide insights into key genetic drivers of diseases and relevant biomarkers. By working together to understand this data, we enable scientists and researchers to make more informed decisions on programs of interest. To learn more about how we can partner together to find your genomic variant solutions, we invite you to click on the link below.
