Submissions for variant NM_003907.3(EIF2B5):c.915G>A (p.Met305Ile)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003555114	SCV004293547	pathogenic	not provided	2023-03-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 305 of the EIF2B5 protein (p.Met305Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 25761052, 34745209). 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 variant disrupts the p.Met305 amino acid residue in EIF2B5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25761052, 25843247, 27651498, 28334938, 34745209). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.