14-75005867-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_014239.4(EIF2B2):c.599G>T(p.Gly200Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,612,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

EIF2B2
NM_014239.4 missense, splice_region

Scores

Splicing: ADA: 0.9810

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 9.62

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 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 14-75005867-G-T is Pathogenic according to our data. Variant chr14-75005867-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75005867-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B2	NM_014239.4 link	c.599G>T	p.Gly200Val	missense_variant, splice_region_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.599G>T	p.Gly200Val	missense_variant, splice_region_variant	Exon 5 of 8	1	NM_014239.4	ENSP00000266126.5		P49770

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000500

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000251

AC:

AN:

251474

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000484

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000510

AC:

745

AN:

1459884

Hom.:

Cov.:

AF XY:

0.000469

AC XY:

341

AN XY:

726374

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000134

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:

0.000647

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000276

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000455

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Oct 17, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the G200V variant results in a complete loss of holocomplex formation (Liu et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26162493, 15776425, 21560189, 14566705, 27159321, 18263758, 31822864, 31589614, 35586607, 29431110, 31980526, 30266093) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 200 of the EIF2B2 protein (p.Gly200Val). This variant is present in population databases (rs113994012, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of leukoencephalopathy with vanishing white matter (PMID: 14566705). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208575). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects EIF2B2 function (PMID: 21560189). For these reasons, this variant has been classified as Pathogenic. -

Oct 27, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Vanishing white matter disease

Pathogenic:5

Jan 29, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dec 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly200Val variant in EIF2B2 has been reported in the compound heterozygous state in multiple individuals with leukoencephalopathy with vanishing white matter and segregated with disease in 2 affected individuals from 1 family (van der Knaap 2003, Ohlenbusch 2005, Maletkovic 2008, Ding 2012, van der Lei 2012, Vanderver 2016, Normand 2018). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 208575) and has been identified in 0.046% (59/129180) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies suggest that the p.Gly200Val variant was incapable of binding to the other EIF2B subunits, supporting an impact on protein function (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 likely pathogenic for autosomal recessive leukoencephalopathy with vanishing white matter. ACMG/AMP Criteria applied: PM3_Strong, PP1_Moderate, PM2_Supporting, PS3_Supporting. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EIF2B2 c.599G>T (p.Gly200Val) missense variant has been reported in five studies in which it is identified in a compound heterozygous state in at least seven patients with childhood ataxia with central nervous system hypomyelination/vanishing white matter, three of whom are related (van der Knaap et al. 2003; Maletkovic et al. 2008; van der Lei et al. 2012; Vanderver et al. 2016) and in one patient with unknown zygosity (Ohlenbusch et al. 2005). Control data are not available for this variant, which is reported at a frequency of 0.00058 in the European-American population of the Exome Sequencing Project. The Gly200 amino acid residue is highly conserved across species and corresponding domains of other EIF2B genes (van der Knaap et al. 2003). Functional studies in HEK293 cells demonstrated that the p.Gly200Val variant is incapable of forming complexes with the other eIF2B subunits (Liu et al. 2011). Based on the evidence, the p.Gly200Val variant is classified as pathogenic for childhood ataxia with central nervous system hypomyelination/vanishing white matter. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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 glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 68 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 2 heterozygotes, 0 homozygotes). (I) 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: 18263758, 22128017, 22430157, 27159321, 30266093). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jun 30, 2023

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.599G>T (p.Gly200Val) 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00025 in 251474 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in EIF2B2 causing Leukoencephalopathy With Vanishing White Matter (0.00025 vs 0.00046), allowing no conclusion about variant significance. c.599G>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Leukoencephalopathy With Vanishing White Matter (e.g. Ohlenbusch_2005, Vanderver_2016, Slynko_2021). These data indicate that the variant is very likely to be associated with disease. When expressed in HEK293 cells, the variant protein was incapable of binding any other subunits to form the mature holoenzyme (Liu_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21560189, 15776425, 33432707, 27159321). Eleven ClinVar submitters have assessed this variant since 2014: four classified the variant as likely pathogenic and seven as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Leukoencephalopathy with vanishing white matter 2

Pathogenic:3

Aug 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 23, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jul 17, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.599G>T (p.G200V) alteration is located in exon 5 (coding exon 5) of the EIF2B2 gene. This alteration results from a G to T substitution at nucleotide position 599, causing the glycine (G) at amino acid position 200 to be replaced by a valine (V). Based on data from gnomAD, the T allele has an overall frequency of 0.02% (68/282866) total alleles studied. The highest observed frequency was 0.05% (59/129180) of European (non-Finnish) alleles. This variant has been identified in conjunction with a EIF2B2 likely pathogenic variant in an individual with clinical features of EIF2B2-related leukoencephalopathy with vanishing white matter (Vanderver, 2016). This alteration was also reported to be in trans with a likely pathogenic variant in an individual with abnormal cerebral white matter morphology, abnormal myelination, and tremor (DECIPHER v.9.32). This amino acid position is highly conserved in available vertebrate species. In one functional study with mutated HEK293 cells, the p.G200V mutant was incapable of binding any other subunits, showing a complete loss of holocomplex formation as seen by SDS-PAGE and western blot analysis (Liu, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

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 -

EIF2B2-related disorder

Pathogenic:1

Nov 17, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EIF2B2 c.599G>T variant is predicted to result in the amino acid substitution p.Gly200Val. This variant has been documented to be causative for leukoencephalopathy with vanishing white matter in several studies (see for example - van der Knaap et al. 2003. PubMed ID: 14566705). This variant is reported in 0.046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-75472570-G-T). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-8.9

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.99

MVP

1.0

MPC

1.5

ClinPred

0.93

GERP RS

5.5

Varity_R

0.99

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.89

SpliceAI score (max)

0.0

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