GAA p.Pro522Ala

The NM_000152.5:c.1564C>G variant in GAA is a missense variant predicted to cause substitution of proline by alanine at amino acid 522 (p.Pro522Ala). This variant has been detected in at least 7 unrelated patients reported to have Pompe disease including four individuals with reported laboratory values demonstrating deficient GAA activity (PMID: 26800218, 33301762, 34072668, Duke University), and three for whom GAA activity was not reported (PMID: 18429042, 37087815) (PP4_Moderate). Of those individuals, 6 were compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LD VCEP: c.784G>A (p.Glu262Lys) (ClinVar Variation ID: 188806, SCV002032128.1) (PMID: 18429042), c.1933G>A (p.Asp645Asn) (ClinVar Variation ID: 188728, SCV001371736.1) (PMID: 18429042), c.1465G>A (p.Asp489Asn) (ClinVar Variation ID: 92465, SCV003852732.1) (PMID: 34072668), and c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 26800218, 37087815, Clinical Diagnostic Laboratory; at least 3 unrelated patients). The phase is not confirmed for any of these individuals. One individual was homozygous for this variant (PMID: 33301762) (PM3_Strong). Another missense variant, c.1564C>T, p.Pro522Ser (ClinVar Variation ID: 972746) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in Ad5-SV40 immortalized human GAA-deficient fibroblast cell line resulted in 0% wild type GAA activity when measured using fluorogenic substrate 4-methylumbelliferyl-α-D glucopyranoside. This was further supported via Western blot analysis demonstrating deficient GAA protein expression (PMID: 18429042) (PS3_Supporting). The computational predictor REVEL gives a score of 0.883 which is above the threshold predicting a damaging (>0.7) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 371277). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PM2_Supporting, PM5_Supporting PS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024).