GAA p.Pro542=

The NM_000152.5:c.1626C>G variant is a synonymous (silent) variant in exon 11 of GAA (p.Pro542=). A minigene assay demonstrated that the variant impacts splicing by creating a de novo donor site in exon 11 as well as activating a cryptic acceptor site in exon 12. This results in the deletion of 11 nucleotides from exon 11 and 46 nucleotides from exon 12. A low level of normal transcript was also detected (PMID 21179066). PVS1_moderate was applied because the resulting deletion is predicted to be in frame (57 nucleotides, 29 amino acids deleted; none of which have been designated by the Lysosomal Diseases VCEP as critical residues). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00000254 (3/1179982 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The variant was found homozygous in one patient with late-onset Pompe disease (PM3_supporting); there was insufficient evidence to apply PP4 (PMID 16917947). There is a ClinVar entry for this variant (Variation ID: 430167). In summary, this variant currently meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Moderate, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 26, 2025).