rs113994049

Positions:

chr3-184137637-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2PM5PP5_Very_StrongBP4

The NM_003907.3(EIF2B5):c.338G>A(p.Arg113His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R113C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

EIF2B5
NM_003907.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24

Conservation

PhyloP100: 3.40

Variant links:

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]

EIF2B5 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-184137636-C-T is described in Lovd as [Pathogenic].

PP5

Variant 3-184137637-G-A is Pathogenic according to our data. Variant chr3-184137637-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184137637-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.089592755). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B5	NM_003907.3 linkuse as main transcript	c.338G>A	p.Arg113His	missense_variant	3/16	ENST00000648915.2	NP_003898.2
EIF2B5	XM_047449148.1 linkuse as main transcript	c.338G>A	p.Arg113His	missense_variant	3/11		XP_047305104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B5	ENST00000648915.2 linkuse as main transcript	c.338G>A	p.Arg113His	missense_variant	3/16		NM_003907.3	ENSP00000497160	P2

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00110

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:

0.000514

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000215

AC:

AN:

251478

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000537

AC:

785

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

389

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000680

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000269

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000514

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000417

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Vanishing white matter disease

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15060152, 26112719). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005945 / PMID: 11704758). Different missense changes at the same codon (p.Arg113Cys, p.Arg113Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000692118 / PMID: 15136673, 34745209). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.338G>A;p.(Arg113His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5945; PMID: 11704758; 18678442; 15136689; 24938145; 18845387; 21560189; 18005052; 18266750; 21307862) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 26112719) - PS3_supporting. The variant is present at low allele frequencies population databases (rs113994049– gnomAD 0.002695%; ABraOM 0.002135 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg113His) was detected in trans with a pathogenic variant PM3_suporte (PMID: 11704758; 18678442; 15136689; 24938145; 18845387; 21560189; 18005052; 18266750; 21307862 ) - PM3_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID: 692118) - PM5. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 10, 2023	Variant summary: EIF2B5 c.338G>A (p.Arg113His) results in a non-conservative amino acid change located in the Translation initiation factor eIF-2B subunit epsilon, N-terminal domain (IPR035543) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EIF2B5 causing Leukoencephalopathy With Vanishing White Matter (0.00021 vs 0.00091), allowing no conclusion about variant significance. c.338G>A has been widely reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Leukoencephalopathy With Vanishing White Matter (example, Slynko_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting decreased tolerance to Endoplasmic Reticulum Stress (ERS) although the magnitude of the reported findings differed significantly from truncated or deletion mutants in EIF2B5 (Chen_2015). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 19, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 27, 2023	The EIF2B5 c.338G>A (p.Arg113His) missense variant has been identified in a homozygous state in at least 30 individuals and in a compound heterozygous state in at least 55 individuals with vanishing white matter disease/leukodystrophy (PMIDs: 15060152; 20975056; 22699478; 22952606; 24938145). Individuals homozygous for the p.Arg113His variant showed a milder form of the disease (PMID: 20975056). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies conducted in patient cells demonstrated that this variant impacts protein function (PMID: 15060152; 22737209; 22952606). Based on the available evidence, the c.338G>A (p.Arg113His) variant is classified as pathogenic for leukoencephalopathy with vanishing white matter. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 28, 2022	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 113 of the EIF2B5 protein (p.Arg113His). This variant is present in population databases (rs113994049, gnomAD 0.04%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (VWM) (PMID: 11704758, 15136689, 18005052, 18266750, 18678442, 18845387, 21307862, 21560189, 22699478, 24938145). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5945). 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: 26112719). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2022	Published functional studies demonstrate a damaging effect with reduction of activity compared to wild-type (Li et al., 2004) and some intolerance to stress of endoplasmic reticulum in oligodendrocytes (Chen et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15776425, 26162493, 31046592, 25525159, 24482476, 11704758, 24938145, 15054402, 15136689, 12707859, 15136673, 15060152, 21560189, 26112719, 28334938, 28914269, 18845387, 18266750, 18678442, 18005052, 30665247, 22699478, 31438897, 31980526, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 29, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 15, 2016	- -

Leukoencephalopathy with vanishing white matter 5

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 11, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Mar 11, 2024	- -

See cases

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 27, 2020	ACMG classification criteria: PS3, PS4, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	Apr 26, 2021	PP5_very strong;PM2_supporting;PM5_moderate;PP2_supporting;PP3_supporting -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2022

The c.338G>A (p.R113H) alteration is located in exon 3 (coding exon 3) of the EIF2B5 gene. This alteration results from a G to A substitution at nucleotide position 338, causing the arginine (R) at amino acid position 113 to be replaced by a histidine (H). This alteration has been detected in the homozygous and compound heterozygous state in multiple individuals diagnosed with leukoencephalopathy with vanishing white matter (VWM disease) (Leegwater, 2001; Fogli, 2004; Turon-Vinas, 2014). This alteration has also been found to segregate among affected homozygotes in multiple families (Labauge, 2009). This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. Functional studies show that this alteration leads to reduced GEF activity (Liu, 2011; Li, 2004; Chen, 2015). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

EIF2B5-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2024

The EIF2B5 c.338G>A variant is predicted to result in the amino acid substitution p.Arg113His. This variant has been reported in both the homozygous state and compound heterozygous state in many patients with leukoencephalopathy with vanishing white matter (Leegwater et al. 2003. PubMed ID: 14572143; Fogli et al. 2004. PubMed ID: 15136673; Liu et al. 2011. PubMed ID: 21560189). Of note, a different missense variant c.337C>T (p.Arg113Cys), affecting the same amino acid residue, has also been reported in patients with leukoencephalopathy with vanishing white matter (Fogli A. et al. 2004. PubMed ID: 15136673). An in vitro functional study revealed that homozygous c.338G>A (p.Arg113His) alleles have around 49 -75% of GEF elf2B activity (Fogli A. et al. 2004. PubMed ID: 15054402). This variant is reported in 0.043% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.090

T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.2

M;.;M

MutationTaster

Benign

0.99

A;A

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.8

N;.;.

REVEL

Uncertain

0.53

Sift

Benign

0.17

T;.;.

Sift4G

Benign

0.11

T;.;.

Polyphen

0.0020

B;.;B

Vest4

0.56

MVP

0.97

MPC

0.35

ClinPred

0.059

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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