The NM_000152.5:c.1781G>A variant in GAA is a missense variant predicted to result in substitution of arginine by histidine at amino acid 594 (p.Arg594His). At least 7 patients with this variant have been reported including two with documented laboratory values showing deficiency of GAA activity (Clinical Diagnostic Laboratory, PMID 33073003) (meeting PP4_Moderate), two on enzyme replacement therapy (meeting PP4 (PMID: 27711114, 30022036), and additional patients reported to have Pompe disease (PMID: 24444888, 25526786, 25998610, 27711114, 30022036, 30155607 ) or identified by newborn screen (PMID: 26889246) (PP4_Moderate). Four probands are compound heterozygous for another variant in GAA that has been classified by the ClinGen Lysosomal Storage Disorders VCEP as pathogenic or likely pathogenic for Pompe disease, including c.1735G>A (p.Glu579Lys) (Clinical Diagnostic Laboratory), 0.5 points; c.-32-13T>G, phase unknown (PMID: 27711114, 30022036), 0.5 points; c.1935C>A (p.Asp645Glu), phase unknown (PMID: 24444888) 0.5 points; c.1194+5G>A, phase unknown (2 patients, could be related) (PMID: 25998610, 27711114, 30022036), 0.25 points. Total 1.75 points (PM3). In addition, three patients are compound heterozygous for the variant and another variant in GAA including c.1194+3G>C (Clinical Diagnostic Laboratory, PMID: 33073003), c.1190C>T (p.Pro397Leu) (PMID: 30155607), c.1562A>T (p.Glu521Val) (PMID: 25526786). The allelic data for these patients will be used in the classification of the other variant and is not included here to avoid circular logic. When expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID: 22644586). This includes 0.1% GAA activity in cells and 1.4% in medium, and evidence of abnormal synthesis and processing on Western blot (PS3_Moderate). The computational predictor REVEL gives a score of 0.927 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The highest population minor allele frequency in a continental population in gnomAD v2.1.1 is 0.000009 (1/111938 alleles) in the European (Non-Finnish) population; the highest population minor allele frequency in any population is 0.0001 in Ashkenzi Jewish (1/9994). This is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another missense variant, c.1781G>C (p.Arg594Pro), at the same position has been reported in individuals with Pompe disease. The classification of c.1781G>A (p.Arg594His) will be used to support the classification of p.Arg594Pro. Therefore, to avoid circular logic, PM5 was not applied. In summary, this variant meets the criteria to be classified as likley pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP on December 16, 2022).