ClinVar

Description

Variant summary: GAA c.1048G>A (p.Val350Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251022 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (9.6e-05 vs 0.0042), allowing no conclusion about variant significance. c.1048G>A has been reported in the literature as heterozygous occurrence, along with a known pathogenic variant, in individual(s) with asymptomatic Pompe disease/Pompe disease presenting with a pure vascular phenotype, and with decreased alpha glucosidase activity in different tissues (Echaniz-Laguna_2015, Quenardelle_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.