rs28939717
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_003907.3(EIF2B5):โc.271A>Gโ(p.Thr91Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (โ โ ).
Frequency
Genomes: ๐ 0.000039 ( 0 hom., cov: 33)
Exomes ๐: 0.000053 ( 0 hom. )
Consequence
EIF2B5
NM_003907.3 missense
NM_003907.3 missense
Scores
7
6
6
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
EIF2B5 (HGNC:3261): (eukaryotic translation initiation factor 2B subunit epsilon) This gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter. [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-184136687-A-G is Pathogenic according to our data. Variant chr3-184136687-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152212Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251470Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135906
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GnomAD4 exome AF: 0.0000527 AC: 77AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39AN XY: 727240
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152330Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74486
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Vanishing white matter disease Pathogenic:5Other:1
not provided, no classification provided | literature only | GeneReviews | - | Dutch founder variant, associated w/relatively mild disease - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 03, 2019 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 24, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 03, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 05, 2020 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 02, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2024 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tรผbingen | Jun 17, 2021 | - - |
Leukoencephalopathy with vanishing white matter 5 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2001 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;L
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;.
REVEL
Pathogenic
Sift
Benign
T;T;.;.
Sift4G
Benign
T;D;.;.
Polyphen
D;.;.;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at