The NM_000152.5:c.2237G>C variant in GAA is a missense variant predicted to result in the substitution of tryptophan by serine at amino acid 746 (p.Trp746Ser). This variant has been reported in at least 11 patients with late onset Pompe disease (LOPD) (PMID: 18425781, 22081099, 24169249, 28490439, 33344388, 34020684), with two having GAA enzyme activity <10% in muscle (PMID: 22081099) (PP4_Moderate). One Chinese patient with LOPD was compound heterozygous for the variant and a nonsense pathogenic variant c.2237G>A (p.Trp746*) at the same nucleotide; however, this patient has a third variant c.503G>A (p.Arg168Gln) with no phase information (PMID: 24169249), so it's not used for PM3 point counting. Another Chinese patient was compound heterozygous for the variant (maternally inherited) and a pathogenic variant c.1935C>A (p.Asp645Glu) (paternally inherited) (PMID: 33344388); and it's not used for PM3 point counting due to the complex phenotype and the lack other evidence supporting the diagnosis of LOPD. A third Chinese individual heterozygous for the variant, a pathogenic variant c.2662G>T (p.Glu888*), and a third variant c.2647-7G>A was detected by genome sequencing as newborn screening; and it's not used for PM3 point counting due to the lack of phenotype information. Six Italian patients (PMID: 22081099) and one Spanish patient (PMID: 34020684) with LOPD were heterozygous for the variant and c.-32-13T>G pathogenic variant with no phase information (1 point, max for homozygous patients) (PM3). Expression of the variant in COS or HEK293 cells resulted in 2% residual GAA activity in medium and 0.1% normal activity in cells and evidence of abnormal GAA synthesis and processing, leading to a Class B ("potentially less severe") classification (PMID: 22644586). However, another in vitro study reported the variant as a "relatively mild mutation" but also class E "probably non-pathogenic" (PMID: 23430493). Functional criteria is not applied due to inconsistent functional classification. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001733 (13/75034) in the African/African American population which is lower than the ClinGen Lysosomal Diseases Variant Curation Expert Panel (LD VCEP) threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.919 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). A different missense variant c.2238G>C (p.Trp746Cys) on the same amino acid has been classified as pathogenic by the LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 188484; 2 star review status) with 7 submitters classifying the variant as pathogenic and 5 as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PM3, PM5, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LD VCEP - Dec. 17, 2024).