ClinVar

Description

Variant summary: GALT c.253-5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes a 3' acceptor site, two predict the variant weakens a 3' acceptor site, and two predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00029 in 277180 control chromosomes, predominantly at a frequency of 0.0029 within the Finnish subpopulation in the gnomAD database. This frequency is about the same that is expected for a pathogenic variant in GALT causing Galactosemia (0.0029 vs 0.0029), that might suggest that the variant is benign. To our knowledge, no occurrence of c.253-5G>A in individuals affected with Galactosemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.