ClinVar

Description

The NM_000152.5:c.2799+2C>A variant in GAA alters the consensus donor splice site of intron 19, the final intron of GAA. The computational splicing predictor SpliceAI gives a score of 0.63 for donor loss, predicting that the variant disrupts splicing. Assuming that this results in skipping of exon 19, an in frame deletion of ~5% of the length of GAA would occur. Of note, the first two nucleotides of the intron are GC, rather than the typical GT (PVS1_Moderate). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of experimental studies to investigate its impact on splicing are not available. Additional variants in this splice region have been identified including c.2799+2C>T (classified by the ClinGen LD VCEP as a VUS), c.2799+4A>G (PMID: 26873529, 30564623) (classified by the ClinGen LD VCEP as likely pathogenic) and c.2799+5G>A (PMID: 28265479) (classified by the ClinGen LD VCEP as a VUS) (PS1_Supporting based on a likely pathogenic variant in the same splice region; Walker et al, 2023; https://www.medrxiv.org/content/10.1101/2023.02.24.23286431v1). There is a ClinVar entry for the variant (Variant ID: 556975). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP: PVS1_Moderate, PS1_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, June 27, 2023)