GAA p.Pro266Ser

The NM_000152.5:c.796C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 266 (p.Pro266Ser). At least seven patients with this variant and features consistent with Pompe disease have been reported. This includes 2 patients with documented laboratory values showing deficient GAA activity (<10% normal or below reference range in leukocytes) (PMID: 17092519, 29124014) (PP4_Moderate). These patients are all compound heterozygous for the variant and another variant in GAA classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, phase unknown, including c.1309C>T (p.Arg437Cys) (PMID: 25526786), c.1316T>A (p.Met439Lys) (PMID: 17092519, 31193175,), c.1935C>A (p.Asp645Glu) (PMID: 28394184) (ClinVar# SCV002032138.1), c.546G>T (PMID: 29124014) (ClinVar# SCV002032139.1), and c.1602_1605delinsAGG (p.Asn535GlyfsTer43) (PMID: 28394184) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001333 (1/70356 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant resulted in 14-18% wild type GAA activity, in two different studies, when expressed in COS cells. (PMID: 18425781, 19862843). Western blot revealed presence of the active 76kDa GAA band, but at a much lower level than wild type (PMID: 19862843). Additional variants at this amino acid positions have been reported (c.797C>T (p.Pro266Leu); c.796C>A (p.Pro266Thr) (PMID: 29451150); these variants have not been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP. The score from the in silico metapredictor REVEL is 0.476 (BP4), which is a single piece of conflicting evidence in comparison with the evidence for pathogenicity. There is a ClinVar entry for this variant (Variation ID:556117, 2 star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, based on the overall evidence, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 2.0.0): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 10, 2026)