rs758746181

chr12-123621850-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 8.00

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]

ACMG classification

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, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B1	NM_001414.4	c.824A>G	p.Tyr275Cys	missense_variant	9/9	ENST00000424014.7

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251448 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135906

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: 52 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37 AN XY: 727170

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.: 32

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Vanishing white matter disease Pathogenic:5

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, no assertion criteria provided	literature only	OMIM	Feb 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
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, 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 -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

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

Jul 27, 2022

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 (gnomAD). This frequency is not higher than expected 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 two compound heterozygous individuals where the pathogenicity of the second allele is not clear. Diagnosis of eIF2B-Related Disorder (Maletkovic_2008) and leukoencephalopathy with VWM/X linked thrombocytopenia were considered for these individuals (Pilania_2020). These reports do not provide unequivocal conclusions about association of the variant with Leukoencephalopathy With Vanishing White Matter. Two publications demonstrated this variant affects protein function and ability to form the complex (examples: Wortham_2015 and Norris_2021). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. 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	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.74		Gain of catalytic residue at S279 (P = 0);
MVP		0.99
MPC		1.0
ClinPred		0.94	D
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

Other links and lift over

dbSNP: rs758746181; hg19: chr12-124106397;