ClinVar

Description

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 267 of the GLDC protein (p.Pro267Leu). This variant is present in population databases (rs138484426, gnomAD 0.01%). This missense change has been observed in individual(s) with nonketotic hyperglycinemia (PMID: 26179960, 28244183; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 556679). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLDC protein function. This variant disrupts the p.Pro267 amino acid residue in GLDC. Other variant(s) that disrupt this residue have been observed in individuals with GLDC-related conditions (PMID: 27362913), which suggests that this may be a clinically significant amino acid residue.