ClinVar

Description

Variant summary: GBE1 c.760A>G (p.Thr254Ala) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain 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 5.4e-05 in 242554 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (5.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.760A>G has been reported in the literature in two individuals affected with Glycogen Storage Disease, Type IV who have reported second mutations (Schene_2018) along with one patient who had only one mutation reported (Said_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two classified as VUS while one classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.