The NM_000152.5:c.658G>T variant is GAA is a missense variant that is predicted to result in the substitution of valine by leucine at amino acid 220 (p.Val220Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00075 (15/19928 alleles) in the East Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS-7 cells, this variant results in normal GAA activity, and the protein is normally synthesized and/or processed (PMID 22644586) (BS3_Supporting). The computational predictor REVEL gives a score of 0.305 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). The variant has been reported in an individual with either suspected Pompe disease or a known carrier, but further details are not available (PMID 22644586). There is a ClinVar entry for this variant (Variation ID: 255365). While there is conflicting evidence, overall, the benign evidence, including functional studies (BS3_Supporting) and in silico data (BP4), outweighs the pathogenic evidence (PM2_Supporting). Therefore, the variant has been classified as likely benign. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting, BP4, BS3_Supporting (modified classification: likely benign, approved by ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 4, 2023).