ClinVar

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg269 amino acid residue in EIF2B5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16864840, 19158808, 29933199). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change does not substantially affect EIF2B5 function (PMID: 21560189). 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 EIF2B5 protein function. This missense change has been observed in individual(s) with leukoencephalopathy with vanishing white matter (PMID: 15776425). This variant is present in population databases (rs113994058, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 269 of the EIF2B5 protein (p.Arg269Gly).