chr14-75005906-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_014239.4(EIF2B2):c.638A>G(p.Glu213Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

EIF2B2
NM_014239.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:2

Conservation

PhyloP100: 8.97

Variant links:

Genes affected

EIF2B2 (HGNC:3258): (eukaryotic translation initiation factor 2B subunit beta) This gene encodes the beta subunit of eukaryotic initiation factor-2B (EIF2B). EIF2B is involved in protein synthesis and exchanges GDP and GTP for its activation and deactivation. [provided by RefSeq, Aug 2011]

EIF2B2 links:

ENSG00000258646 (HGNC:):

ENSG00000258646 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 14-75005906-A-G is Pathogenic according to our data. Variant chr14-75005906-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 4336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75005906-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B2	NM_014239.4 link	c.638A>G	p.Glu213Gly	missense_variant	Exon 5 of 8	ENST00000266126.10	NP_055054.1	P49770Q53XC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B2	ENST00000266126.10 link	c.638A>G	p.Glu213Gly	missense_variant	Exon 5 of 8	1	NM_014239.4	ENSP00000266126.5		P49770

Frequencies

GnomAD3 genomes

AF:

0.0000722

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251480

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1461346

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000855

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Vanishing white matter disease

Pathogenic:4Other:2

Sep 21, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Dutch founder variant, associated w/relatively mild disease -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 05, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:3

Mar 04, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jun 10, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Leukoencephalopathy with vanishing white matter 2

Pathogenic:2

Aug 18, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

See cases

Pathogenic:1

Sep 01, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3, PM3, PP3 -

Leukoencephalopathy with vanishing white matter 1

Pathogenic:1

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

EIF2B2-related disorder

Pathogenic:1

Jan 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.028

D;D

Polyphen

0.95

P;.

Vest4

0.95

MVP

1.0

MPC

1.3

ClinPred

0.89

GERP RS

5.5

Varity_R

0.93

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over