ClinVar Genomic variation as it relates to human health

The p.Thr91Ala variant in EIF2B5 has been reported in the homozygous or compound heterozygous state in at least 15 individuals with leukoencephalopathy with vanishing white matter and segregated with disease in 3 affected individuals from 3 families (Leegwater 2001, Li 2004, Kantor 2005, Horzinski 2010, van der Lei 2010, Liu 2011). It has also been reported by other clinical laboratories in ClinVar (Variation ID # 5942) and has been identified in 0.008% (10/129180) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Li 2004, Dietrich 2005, Horzinski 2010, Liu 2011). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive leukoencephalopathy with vanishing white matter. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Moderate, PS3_Supporting.

The EIF2B5 c.271A>G (p.Thr91Ala) missense variant has been well-described in the literature as a pathogenic variant for childhood ataxia with central nervous system hypomyelination and vanishing white matter, which is also known as leukoencephalopathy with vanishing white matter (VWM). Leegwater et al. (2001) studied 41 individuals with VWM from 35 families, and found the p.Thr91Ala variant in a homozygous state in seven individuals (including two sibling pairs), and in a compound heterozygous state in four individuals. The p.Thr91Ala variant was found as part of a shared ancestral haplotype. Van der Lei et al. (2010) compared the phenotypes 184 individuals with VWM and a few select genotypes, including eight individuals homozygous for the p.Thr91Ala variant, and seven individuals compound heterozygous for the p.Thr91Ala variant and a missense variant. The authors suggest that the variable VWM phenotype is determined by the combination of both variants, although the p.Thr91Ala variant is generally associated with an intermediate/moderate phenotype. Functional studies demonstrated that the p.Thr91Ala variant protein has a reduced ability to form eIF2B holocomplexes and that holocomplexes containing the p.Thr91Ala variant had reduced, but not absent, enzymatic activity (Li et al. 2004; Liu et al. 2011). The p.Thr91Ala variant was absent from at least 210 control chromosomes and is reported at a frequency of 0.00007 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Thr91Ala variant is classified as pathogenic for childhood ataxia with central nervous system hypomyelination and vanishing white matter. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 91 of the EIF2B5 protein (p.Thr91Ala). This variant is present in population databases (rs28939717, gnomAD 0.009%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 11704758, 15136673, 20975056, 21560189). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5942). 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 not expected to disrupt EIF2B5 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EIF2B5 function (PMID: 15060152). For these reasons, this variant has been classified as Pathogenic.

Published functional studies indicate that T91A is associated with a decrease in guanine nucleotide-exchange factor activity (PMID: 21560189); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 11704758, 21560189)

Dutch founder variant, associated w/relatively mild disease