Submission Details

The relationship between GLA and Fabry disease, an X-linked lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of March 3rd, 2017. Deficiency of the gene product, alpha-galactosidase A, was first reported in males with Fabry disease in 1967 (Brady et al; PMID 6023233), and variants in GLA were first associated with this disease in 1989 (Bernstein et al, PMID 2539398). Over 400 unique variants, including missense, nonsense, splice site, frameshift, in-frame deletions, and complex rearrangements, have been reported in humans (reviewed in Gal et al, 2006, PMID 21290673; Mehta, 2017, PMID 20301469). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twenty-five variants were curated in 25 probands from 3 publications (Bernstein et al, 1989, PMID 2539398; Topaloglu et al, 1989, PMID 10666480; Shimotori et al, 2008, PMID 18205205). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is loss of function. This gene-disease association is supported by the function of the gene product (Brady et al, 1967, PMID 6020428) animal models and rescue (Oshima et al, 1997, PMID 9122231; Taguchi et al, 2013, PMID 24094090), and studies of the clinical impact of enzyme replacement therapy in humans (Beck et al, 2015, PMID 26937390). In summary, GLA is definitively associated with Fabry disease. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.