GAA p.Pro161fs

This variant, c.482_483del (p.Pro161GlnfsTer15), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001836 in the European non-Finnish population, meeting PM2. Five individuals have been reported with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4. Of these individuals, three are compound heterozygous for c.-32-13T>G (PMID 9196050, 26873529), one is compound heterozygous for c.-32-3C>A (PMID 21550241; a patient with a similar description is reported in PMIDs 30155607, 21803581), and the second variant was unidentified in the remaining patient (PMID 9196050). The phase of the variants is unknown in these cases. The in trans data for the patient who is compound heterozygous for c.-32-3C>A will be used in the assessment of that variant and was not included here in order to avoid a circular argument. Therefore, PM3_Supporting is met. Additional patients have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) or full HGVS nomenclature was not provided (PMIDs 11071489, 28648663, 32248831). There is a ClinVar entry for this variant (Variation ID: 596146, 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.