Fabry disease is a rare, X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, which encodes the enzyme alpha-galactosidase A (α-Gal A). This enzyme is critical for the catabolism of globotriaosylceramide (Gb3), a glycosphingolipid. Loss of α-Gal A activity results in Gb3 accumulation within lysosomes, leading to widespread cellular dysfunction.
Clinically, Fabry disease is highly heterogeneous. It can manifest early in life with classic symptoms such as acroparesthesias, angiokeratomas, hypohidrosis, and corneal opacity, or later with progressive renal failure, cardiomyopathy, and cerebrovascular complications. The phenotypic variability underscores the necessity of precise molecular diagnosis, which informs prognosis, family screening, and increasingly, eligibility for enzyme replacement or gene therapies.
The Critical Role of GLA Gene Variant Interpretation
Given the diversity of clinical presentations, accurate interpretation of GLA gene variants is paramount. However, the GLA gene exhibits high allelic heterogeneity, with hundreds of reported variants spanning missense, nonsense, frameshift, and splicing alterations. Differentiating between benign polymorphisms, variants of uncertain significance (VUS), and truly pathogenic variants requires a comprehensive approach combining genomic data, functional studies, and population databases.
Without high-quality variant interpretation, patients risk delayed diagnosis or misdiagnosis — potentially missing the window for early intervention. This highlights the role of sophisticated genomic tools and meticulous curation efforts to bridge gaps in clinical understanding.
Our Approach: Comprehensive GLA Variant Curation and Insights from ACMG
At Genomenon, we recognized the complexity of GLA variant interpretation and addressed this challenge through a rigorous, systematic approach in our Mastermind Genomic Intelligence Platform.
Leveraging the full scope of real-world evidence (RWE) available in the scientific literature, our science team reviewed and curated 1,634 publications reporting on GLA variants. Each variant was assessed using established ACMG/AMP guidelines, integrating functional data, case-level clinical evidence, population frequency, and computational predictions to ensure robust and reliable classification. This effort directly supports precision medicine by providing clinicians with clear, actionable variant interpretations and empowers researchers to deepen their understanding of the genetic architecture of Fabry disease.
Our findings were recently presented at the 2025 ACMG conference in our poster titled:
“Systematic Literature Review of GLA Variants Uncovers Additional Fabry Disease-Causing Variants.”
In this study, we analyzed 1,677 unique GLA variants and a significant portion of these variants were initially classified as variants of uncertain significance (VUS), highlighting the ongoing challenges in interpreting their clinical impact.
To address this, we applied a novel enzyme activity threshold, drawing from robust in vitro and in vivo functional studies. We established that GLA enzyme activity levels below 5.5% in vitro and below 3.0% in vivo reliably indicate pathogenicity. Using these cutoffs to define thresholds for deleterious functional consequences to protein function, 71 out of 126 VUS variants associated with Fabry patient cases and with published functional studies were promoted from VUS to pathogenic classification.
Implications for Clinical Practice and Research
Our work reinforces the necessity of comprehensive, evidence-based variant curation to advance clinical diagnostics in Fabry disease. By combining extensive literature analysis with functional assay data, we provide a more definitive understanding of GLA gene variation, reducing diagnostic uncertainty and enabling earlier, more accurate identification of affected individuals.
To further support the clinical and research community, Genomenon is offering free access to curated insights on the GLA gene throughout April and May. By making this data openly available, we aim to accelerate the identification of pathogenic variants, assist healthcare providers in making informed diagnostic and treatment decisions, and empower researchers with high-quality evidence for ongoing studies. This initiative underscores our commitment to advancing rare disease understanding and ensuring that critical genomic insights reach those who need them most.
For clinicians, this means greater confidence in interpreting patient genotypes. For researchers, it offers a deeper insight into genotype-phenotype correlations and potential targets for emerging therapies. For patients and their families, it offers the hope of faster answers and more precise care.
Conclusion: Bridging the Gap Between Uncertainty and Actionable Insights
The integration of exhaustive literature curation with functional data has allowed us to elevate the clinical utility of GLA variant interpretation. Through our Mastermind platform and the insights shared at ACMG, we continue to illuminate the genetic underpinnings of Fabry disease, supporting the global effort toward timely diagnosis and effective treatment.
As genomic medicine advances, we remain committed to expanding this approach to other complex diseases, ensuring that no patient is left behind in the pursuit of precision healthcare.
Take advantage of free access to the GLA gene in Mastermind — dive into expertly curated insights and support your clinical or research efforts this April and May.
