The NM_000152.5:c.1124G>T (p. Arg375Leu) variant in GAA is a missense variant predicted to cause substitution of arginine by leucine at amino acid 375. This variant has been detected in at least 4 individuals with Pompe disease. Of those, at least 2 patients with late onset Pompe disease from Italy are documented, with reduced GAA activity in leukocytes or muscle. These patients are compound heterozygous, phase unknown, for c.1124G>T (p.Arg375Leu) and the pathogenic variant c.-32-13T>G i(PMIDs: 24158270, 22081099). One proband with severe infantile Pompe was reported to be compound heterozygous for the variant and a variant classified by the ClinGen LSD VCEP as pathogenic, c.784G>A (p.Glu262Lys), confirmed in trans, and another patient with infantile-onset Pompe disease was homozygous for the variant (PM3_Strong; PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001787 (2/111942 alleles) in the European (non-Finnish) population, which is lower than threshold for PM2_Supporting (<0.001), meeting PM2_Supporting. Expression of c.1124G>T (p.Arg375Leu) variant in Ad5-SV40 immortalized human GAA deficient fibroblast cell line demonstrated 0.3% of wild type GAA activity (PMID: 18429042) (PS3_supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7 (PP3). Another missense variant [c.1124G>A (p.Arg375His) in the same codon has been reported in two patients from Asia with Pompe disease (PMID: 21757382, 21484825) . However this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is ClinVar entry for the variant (Variation ID: 283230, two star review status) with six submitters classifying the variant as Pathogenic/Likely Pathogenic. In summary, c.1124G>T (p.Arg375Leu) variant meets the criteria to be classified as likely pathogenic for Pompe disease, based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel. ACMG/AMP criteria applied (specifications version 2.0): PM3_strong ; PP4_Moderate; PS3_supporting; PM2_Supporting, PP3. (Classification approved by the ClinGen LSD VCEP on December 6, 2022)