ClinVar

Description

Variant summary: GAA c.1123C>T (p.Arg375Cys) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, TIM barrel domain (IPR000322) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 248608 control chromosomes (gnomAD). c.1123C>T has been reported in the literature in newborns who had abnormal newborn screening and also in an individual affected with hyperCKemia (examples : Gemelli_2020, Goomber_2022, Kubaski_2023) . These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1124G>T, p.Arg375Leu), supporting the critical relevance of codon 375 to GAA protein function. In an invitro functional study, the variant resulted in reduced activity (Goomber_2022). The following publications have been ascertained in the context of this evaluation (PMID: 34687219, 36246652, 37507255, 24627108). ClinVar contains an entry for this variant (Variation ID: 290225). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.