GAA p.Pro522Ser

The NM_000152.5:c.1564C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 522 (p.Pro522Ser). Two probands with a confirmed diagnosis of IOPD have been reported with this variant (PMID: 32518148, 38250073), both CRIM-positive, one with documented symptoms of IOPD and the other on ERT (PP4_Moderate). Both probands are compound heterozygotes for the variant and other variants that have yet to be classified by the ClinGen Lysosomal Diseases VCEP (PM3_Not Met). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00001761 in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2, meeting this criterion. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe"). This includes 0.8% GAA activity in cells and 0.8% in medium, and evidence of abnormal synthesis and processing on Western blot (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.932 which is higher than the ClinGen LD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 972746). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP: PP4_Moderate, PS3_Moderate, PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024).