rs758746181

Positions:

chr12-123621850-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001414.4(EIF2B1):c.824A>G(p.Tyr275Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,461,758 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

EIF2B1
NM_001414.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 8.00

Variant links:

Genes affected

EIF2B1 (HGNC:3257): (eukaryotic translation initiation factor 2B subunit alpha) 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, Oct 2009]

EIF2B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 12-123621850-T-C is Pathogenic according to our data. Variant chr12-123621850-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217281.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B1	NM_001414.4 linkuse as main transcript	c.824A>G	p.Tyr275Cys	missense_variant	9/9	ENST00000424014.7	NP_001405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B1	ENST00000424014.7 linkuse as main transcript	c.824A>G	p.Tyr275Cys	missense_variant	9/9	1	NM_001414.4	ENSP00000416250	P1	Q14232-1
EIF2B1	ENST00000539951.5 linkuse as main transcript	c.*100A>G		3_prime_UTR_variant	7/7	5		ENSP00000438060

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251448

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135906

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:

0.000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727170

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:

0.000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Vanishing white matter disease

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	May 08, 2020	A heterozygous missense variation in exon 9 of the EIF2B1 gene that results in the amino acid substitution of Cysteine for Tyrosine at codon 275 was detected. The observed variant c.824A>G (p.Tyr275Cys) lies in the initiation factor 2 subunit family domain of the EIF2B1 protein and has previously been reported in a compound heterozygous state in a patient affected with eIF2B-related disorders (Maletkovic et al. 2008). The variant has not been reported in the 1000 genomes and has a minor allele frequency of 0.009% in the ExAC databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT, and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.Y275C in EIF2B1 (NM_001414.3) has been previously reported in compound heterozygous form with G204del in a similarly affected patient. Protein modelling suggested a possible loss of hydrogen bonding interaction or formation of an unwanted disulfide bond (Maletkovic et al, 2008). The variant has been submitted to ClinVar as Pathogenic based on the above publication but no functional assays have confirmed a deletrious effect of the above variant. There is a large physicochemical difference between tyrosine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.Y275C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The tyrosine residue at codon 275 of EIF2B1 is conserved in all mammalian species. The nucleotide c.824 in EIF2B1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	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). A single missense variant has some functional evidence of having a gain of function mechanism (PMID: 26285592). (I) 0106 - This gene is associated with autosomal recessive disease. However, there is emerging evidence of heterozygous de novo variants causing a dominant form of disease in babies with neonatal diabetes and transient hepatic dysfunction (PMID: 31882561). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 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 (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic, and observed in a homozygous individual with vanishing white matter (VWM) disease, and at least three compound heterozygous individuals with leukodystrophy, cerebral atrophy and VWM disease. One of these individuals also had thrombocytopenia and was hemizygous for a variant in the WAS gene (ClinVar, PMID: 18263758; PMID: 32865661, PMID: 34663487). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 cells have demonstrated significant reductions in eIF2Ba binding (PMID: 26285592). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 17, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects EIF2B1 function (PMID: 26285592, 33334879). 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 expected to disrupt EIF2B1 protein function. ClinVar contains an entry for this variant (Variation ID: 217281). This missense change has been observed in individual(s) with clinical features of EIF2B1-related conditions and/or vanishing white matter disease (PMID: 18263758, 32865661, 34663487). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs758746181, gnomAD 0.06%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 275 of the EIF2B1 protein (p.Tyr275Cys). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 26, 2024

Variant summary: EIF2B1 c.824A>G (p.Tyr275Cys) 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 7.2e-05 in 251448 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EIF2B1 causing Leukoencephalopathy With Vanishing White Matter (7.2e-05 vs 0.00016), allowing no conclusion about variant significance. c.824A>G has been reported in the literature in individuals affected with EIF2B-related disorders in the compound heterozygous and homozygous states (Maletkovik_2008, Pilania_2020, Shivaram_2022). These data indicate that the variant may be associated with disease.Two publications demonstrated this variant affects protein function, reducing complex formation (examples: Wortham_2015 and Norris_2021). The following publications have been ascertained in the context of this evaluation (PMID: 18263758, 33334879, 32865661, 26285592, 34663487). ClinVar contains an entry for this variant (Variation ID: 217281). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.74

Gain of catalytic residue at S279 (P = 0);

MVP

0.99

MPC

1.0

ClinPred

0.94

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.92

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