ClinVar Genomic variation as it relates to human health

Variant summary: EIF2B2 c.638A>G (p.Glu213Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251480 control chromosomes. c.638A>G has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Leukoencephalopathy With Vanishing White Matter (examples- Leegwater_2001, Fogli_2004). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence that homozygous cell lines with the variant demonstate reduced EIF2B2 guanine nucleotide exchange factor activity (examples- Li_2004, Fogli_2004). One clinical diagnostic laboratory and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both submitters cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 213 of the EIF2B2 protein (p.Glu213Gly). This variant is present in population databases (rs104894425, gnomAD 0.009%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 11704758, 12707859, 15136673, 21560189). ClinVar contains an entry for this variant (Variation ID: 4336). 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 EIF2B2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EIF2B2 function (PMID: 15060152). For these reasons, this variant has been classified as Pathogenic.

The EIF2B2 c.638A>G (p.Glu213Gly) variant has been reported in three studies in which it is found in a total of 24 individuals with childhood ataxia with central nervous system hypomyelination/vanishing white matter including 15 homozygotes (including 11 siblings from five families) and nine compound heterozygotes (Leegwater et al. 2001; Fogli et al. 2004; Ohlenbusch et al. 2005). The p.Glu213Gly variant was absent from 307 controls (Leegwater et al. 2001, Fogli et al. 2004, Ohlenbusch et al. 2005) and is reported at a frequency of 0.000087 in the European (non-Finnish) population of the Genome Aggregation Database. Li et al. (2004) demonstrated in transfected HEK 293 cells that the p.Glu213Gly variant does not affect assembly of the EIF2B translation initiation factor complex but it does decrease EIF2B2 enzyme activity to 40-60% of wild type. In vivo assays also showed that the p.Glu213Gly variant enhanced eIF2 binding (Li et al. 2004). Based on the collective evidence, the p.Glu213Gly variant is classified as pathogenic for childhood ataxia with central nervous system hypomyelination/vanishing white matter.

ACMG classification criteria: PS3, PM3, PP3

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with leukoencephalopathy with vanishing white matter (MIM#603896). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 11 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated IF-2B domain (NCBI, DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been found in at least ten individuals with vanishing white matter and classified as pathogenic by diagnostic laboratories in Clinvar (PMID: 15136673, 31438897). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

In vitro studies have shown that in the homozygous state E213G enzyme activity was reduced by approximately 50%, and when reported with a second EIF2B2 variant (phase unknown) reduced translation was observed (Liu et al., 2011; Moon et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31438897, 33432707, 21560189, 22729508, 20958979, 18263758, 12707859, 16823698, 11704758, 15776425, 29632131, 31589614)

EIF2B2 NM_014239.3 exon 5 p.Glu213Gly (c.638A>G): This variant has been reported in the literature in multiple individuals with features of leukodystrophy/vanishing white matter (at least 10 individuals in the homozygous state, 6 individuals in the compound heterozygous state), segregating with disease in at least 3 affected family members (Leegwater 2001 PMID:11704758, Fogli 2004 PMID:15136673, Ohlenbusch 2005 PMID:15776425). This variant is present in 10/129186 European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/14-75472609-A-G). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar (Variation ID:4336). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies support that this variant will impact the protein (Li 2004 PMID:15060152, Liu 2011 PMID:21560189). In summary, this variant is classified as pathogenic.

Variant confirmed as disease-causing by referring clinical team

The EIF2B2 c.638A>G variant is predicted to result in the amino acid substitution p.Glu213Gly. This variant was reported in the homozygous or compound heterozygous states in individuals with leukoencephalopathy with vanishing white matter (see, for example, Leegwater et al. 2001. PubMed ID: 11704758; Liu et al. 2011. PubMed ID: 21560189; Sambati et al. 2012. PubMed ID: 22729508; Fogli et al. 2004. PubMed ID: 15054402). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

Dutch founder variant, associated w/relatively mild disease

Variant interpretted as pathogenic and reported on 03/14/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.