GAA p.Pro451Arg

The NM_000152.5:c.1352C>G variant in GAA is a missense variant predicted to result in the substitution of proline by arginine at amino acid 451 (p.Pro451Arg). The highest population minor allele frequency in gnomAD v4.1.0 is 0.004835 (363/75080) alleles, including 4 homozygotes) in the African/African-American population. This allele frequency meets the ClinGen LD VCEP threshold (>0.005) for BS1 (after rounding up). The variant was reported in a patient with limb-girdle muscle weakness but was not thought to be causative of the symptoms (PMID: 29149851). The variant was also reported in a patient with autism spectrum disorder but no reported diagnosis of Pompe disease (PMID: 37492102). The computational predictor REVEL gives a score of 0.449 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function, and SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281330). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert panel on May 20, 2025)