GAA p.Trp367Arg

The NM_000152.5: c.1099T>C variant in GAA is a missense variant resulting in the substitution of tryptophan by arginine at amino acid 367 (p.Trp367Arg). This variant has been reported in at least 4 patients with a diagnosis of infantile onset Pompe disease (IOPD) presenting with symptoms including cardiomegaly and hypotonia, documented deficient GAA activity and/or on enzyme replacement therapy (PMID: 17056254‚ 22658377, 23787031, 25139343, 31510962); it was also reported in one patient with late-onset Pompe disease (LOPD) (PMID: 22958975) (PP4_Moderate). Three patients were reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP. In these patients, the second variant was either c.-32-13T>G (phase unconfirmed, 0.5 pt) (PMID: 22958975), c.1802C>T (p.Ser601Leu) (confirmed in trans, 1 pt) (PMID: 22658377, 23401069, 23787031, 25139343, 29122469, 31904026) or c.1942G>A (p.Gly648Ser) (confirmed in trans, 1 pt) PMID: 31510962). One patient was reported to be homozygous for the variant (PMID: 17056254). An additional patient was compound heterozygous for the variant and c.625T>C (p.Tyr209His), phase unconfirmed (PMID: 40952111). The allelic data from this patient will be used in the classification of c.625T>C (p.Tyr209His) and is not included here to avoid circular logic. Total points: 3 (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 8.5e-7 (1/1179976 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity without mature processed GAA protein on immunoblots, indicating a negative impact on GAA function (PMID: 19862843) (PS3_Supporting). The computational meta-predictor REVEL has a score of 0.944 for the variant, which is above the threshold of 0.7, indicating a negative impact on GAA function (PP3). Another missense variant, c.1099T>G (p.Trp367Gly), in the same codon has been reported in a patient with LOPD (PMID: 29124014). However, the data for p.Trp367Arg will be used in the assessment of p.Trp367Gly and therefore PM5 is not met here in order to avoid circular argument. There is a ClinVar entry for this variant (Variation ID: 555820). Given the multiple reports of patients with features specific for Pompe disease and multiple lines of evidence, including high REVEL score and availability of functional data, the VCEP elected to elevate the classification from Likely Pathogenic to Pathogenic. In summary, this variant was classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting (classification modified to pathogenic). (Classification approved by the ClinGen ClinGen Lysosomal Diseases Variant Curation Expert Panel, on September 1, 2026).