Submissions for variant NM_003907.3(EIF2B5):c.271A>G (p.Thr91Ala)

gnomAD frequency: 0.00004  dbSNP: rs28939717

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255738	SCV000321595	pathogenic	not provided	2016-06-13	criteria provided, single submitter	clinical testing	The T91A variant in the EIF2B5 gene has been reported previously in multiple unrelated individuals with leukoencephalopathy with vanishing white matter who harbored a second mutation on the other allele (Leegwater et al., 2001). Functional studies indicate that T91A is associated with a decrease in guanine nucleotide-exchange factor activity (Liu et al., 2011). The T91A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The 1000 Genomes Project reports T91A was observed in 1/1006 alleles from individuals of European background. The T91A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T91A as a pathogenic variant.
Illumina Laboratory Services, Illumina	RCV000006305	SCV000442319	pathogenic	Vanishing white matter disease	2017-04-27	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000255738	SCV001200579	pathogenic	not provided	2023-11-02	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000006305	SCV001365777	pathogenic	Vanishing white matter disease	2019-06-03	criteria provided, single submitter	clinical testing	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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000006305	SCV001448788	likely pathogenic	Vanishing white matter disease	2017-03-24	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255738	SCV001762186	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000006305	SCV002777924	pathogenic	Vanishing white matter disease	2021-09-03	criteria provided, single submitter	clinical testing
OMIM	RCV003221408	SCV000026487	pathogenic	Leukoencephalopathy with vanishing white matter 5	2001-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000006305	SCV000996323	not provided	Vanishing white matter disease		no assertion provided	literature only	Dutch founder variant, associated w/relatively mild disease
Natera, Inc.	RCV000006305	SCV002079135	pathogenic	Vanishing white matter disease	2020-07-05	no assertion criteria provided	clinical testing