rs113994049

chr3-184137637-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2 PM5 PP5_Very_Strong BP4

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 Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 3.40

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]

ACMG classification

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 ClinVar as [Likely_pathogenic]. Clinvar id is 692118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	UniProt
EIF2B5	NM_003907.3	c.338G>A	p.Arg113His	missense_variant	3/16	ENST00000648915.2
EIF2B5	XM_047449148.1	c.338G>A	p.Arg113His	missense_variant	3/11

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152150 Hom.: 0 Cov.: 32

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: 54 AN: 251478 Hom.: 0 AF XY: 0.000250 AC XY: 34 AN XY: 135918

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.: 0 Cov.: 31 AF XY: 0.000535 AC XY: 389 AN XY: 727244

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: 41 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74456

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.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vanishing white matter disease Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 28, 2022	- -
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	Genetics and Molecular Pathology, SA Pathology	Nov 19, 2020	- -
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	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	MGZ Medical Genetics Center	Apr 06, 2022	- -
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	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Pathogenic:6

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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	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	Athena Diagnostics	Oct 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 29, 2015	- -

Leukoencephalopathy with vanishing white matter 5 Pathogenic:3

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

See cases Pathogenic:2

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 -
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 -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.090	T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	M;.;M
MutationTaster	Benign	0.99	A;A
PrimateAI	Benign	0.28	T
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	T
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

Other links and lift over

dbSNP: rs113994049; hg19: chr3-183855425;