The NM_000152.5:c.2174G>A variant in GAA is a missense variant predicted to cause substitution of Arg by Gln at amino acid 725 (p.Arg725Gln). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. It only has been reported in one case with a positive newborn screening result for GAA-related disease, in which has concurrence of c.664 G>A (benign or likely benign) (PMID: 23430949). Thus there is insufficient data to apply PP4 nor PM3. Another missense variant c.2173C>T (p.Arg725Trp) (PMID: 8401535, 17616415, 19588081, 28648663, 30155607; ClinVar Variation ID: 4024), in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP. Thus PM5 is applied. There is a ClinVar entry for this variant (Variation ID: 555727, 1 star review status) with 2 submitters classifying the variant as Uncertain significance, and 2 submitters classifying it as Likely Pathogenic. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP3, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 3, 2023).