The relationship between GAA and glycogen storage disease type II (GSD II; Pompe disease; acid maltase deficiency) was evaluated using the ClinGen Clinical Validity Framework as of June 26, 2017. Deficiency of the gene product, acid alpha-glucosidase (acid maltase) was first reported in individuals with GSD II by Hers in 1963, and variants in GAA were first associated with this disease 1991 (Hermans et al, MID 8401535; Zhong et al, 1652892; Martinuik et al, 1684505). Over 800 unique variants, including missense, nonsense, splice site, in frame insertions and deletions, frameshift, large deletions, and complex rearrangements have been reported in humans (http://cluster15.erasmusmc.nl/klgn/pompe/mutations.html?lang=en). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Fourteen variants were curated in 10 probands in 9 publications (Zhong et al, 1991, PMID 1652892; Hermans et al, 1993, PMID 8094613; Huie et al, 1994, PMID 7981676; Boerkoel et al, 1995, PMID 7717400; Huie et al, 1998, PMID 9535769; Pipo et al, 2003, PMID 14643388; Palmer et al, 2007, PMID 17056254; Oba-Shinjo et al, 2009, PMID 19588081; Rohrbach et al, 2010, PMID 20882352 ). 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 (Brown et al, 1965, PMID 4286143), abnormal synthesis, transport and processing, and deficient activity of acid alpha-glucosidase in cells from patients and non-patient cells expressing GAA variants (Hermans et al, 1991, PMID 1856189; Reuser et al, 1997, PMID 3108320; Umapathysivam et al, 2000, PMID 10973860; Bali et al, 2011, PMID 21484825), animal models (Raben et al, 1998, PMID 9668092), gene therapy in animal models (Fraites et al, 2002, PMID 11991748) and studies of the clinical impact of enzyme replacement therapy in humans (Kishnani et al, 2006, PMID 1680134). In summary, GAA is definitively associated with glycogen storage disease type II. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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