ClinVar Genomic variation as it relates to human health

Variant summary: GALT c.152G>T (p.Arg51Leu) results in a non-conservative amino acid change located in the N-terminal domain (IPR005849) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251422 control chromosomes (gnomAD). c.152G>T has been reported in the literature in multiple individuals affected with Galactosemia (e.g. Tyfield_1999, Zekanowski_2001, Boutron_2012, Bech_2018, Jezela-Stanek_2021). These data indicate that the variant is very likely to be associated with disease. Molecular modelling has suggested that this variant is likely to impact the structure of the GALT protein (e.g. Facchiano_2010). However, to our knowledge, an effect on protein function has yet to be evaluated with experimental studies. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg51 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15841485, 31954591). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALT protein function. ClinVar contains an entry for this variant (Variation ID: 1470556). This missense change has been observed in individual(s) with galactosemia (PMID: 22944367, 29892033, 34030713). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 51 of the GALT protein (p.Arg51Leu).