GAA p.Pro285Arg

The NM_000152.5:c.854C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 285 (p.Pro285Arg). The highest population minor allele frequency in gnomAD v4.0.1 is 0.000001784 (1/ 1120816 alleles) in the European non-finish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least two probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant, both with documented deficiency of GAA activity (PMID: 28196920, 19862843). One proband had juvenile-onset (after 1 year of age) (PMID: 14695532) (PP4_Moderate). One patient was compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811); phase unconfirmed (PMID: 12213618, 14695532). Another individual is compound heterozygous for the variant and c.2303C>T (Pro768Leu) (PMID: 28196920). The allelic data from this patient will be used toward the classification of p.Pro768Leu and is not included here to avoid circular logic. Additional reports of this variant identified in newborn screening (PMID: 28196920, 12213618, 14695532, 19862843). Total 0.5 points (PM3_Supporting). Expression of the variant in COS cell type resulted in 2-10% (~ 5%) of wild-type GAA activity and evidence of abnormal GAA synthesis and processing (PMID: 19862843, 14695532, 19862843). The variant was described as Class C (“less severe”), indicating that this variant may impact protein function (PMID: 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.883, which is above the threshold of 0.7, evidence that correlates with impact on GAA function (PP3). Another missense variant (c.853C>T, p.Pro285Ser) (PMID: 18425781, 21484825, 21550241; ClinVar Variation ID 281052) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 526532; 2-star review status) with four submitters classifying the variant as pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP4_Moderate, PM3_Supporting, PS3_Moderate, PM5_Supporting, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 18, 2025)