ClinVar Genomic variation as it relates to human health
NM_001414.4(EIF2B1):c.824A>G (p.Tyr275Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001414.4(EIF2B1):c.824A>G (p.Tyr275Cys)
Variation ID: 217281 Accession: VCV000217281.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 123621850 (GRCh38) [ NCBI UCSC ] 12: 124106397 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 22, 2015 Feb 14, 2024 Jun 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001414.4:c.824A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001405.1:p.Tyr275Cys missense NM_001414.3:c.824A>G NC_000012.12:g.123621850T>C NC_000012.11:g.124106397T>C NG_015862.1:g.16927A>G - Protein change
- Y275C
- Other names
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- Canonical SPDI
- NC_000012.12:123621849:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Uncertain function
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00007
Exome Aggregation Consortium (ExAC) 0.00009
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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EIF2B1 | - | - |
GRCh38 GRCh37 |
221 | 311 | |
LOC126861664 | - | - | - | GRCh38 | - | 67 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Sep 2, 2022 | RCV000201219.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 17, 2023 | RCV003556247.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 27, 2022 | RCV002282035.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(May 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy with vanishing white matter 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001469118.1
First in ClinVar: Jan 30, 2021 Last updated: Jan 30, 2021 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Difficulty walking (present) , Cerebral atrophy (present) , Cerebellar atrophy (present) , Leukodystrophy (present)
Age: 40-49 years
Sex: male
Ethnicity/Population group: Hindu
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Leukoencephalopathy with vanishing white matter 1
Affected status: yes
Allele origin:
inherited
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002053961.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Uncertain significance
(Jul 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002570705.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy with vanishing white matter 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769506.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy with vanishing white matter 1
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820258.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Febrile seizure (within the age range of 3 months to 6 years) (present) , Spasticity (present) , Spastic gait (present)
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Likely pathogenic
(Jun 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004295439.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Feb 01, 2008)
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no assertion criteria provided
Method: literature only
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LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000255951.3
First in ClinVar: Oct 22, 2015 Last updated: Apr 23, 2023 |
Comment on evidence:
For discussion of the c.824A-G transition in the EIF2B1 gene, resulting in a tyr275-to-cys (Y275C) substitution that was found in compound heterozygous state in a … (more)
For discussion of the c.824A-G transition in the EIF2B1 gene, resulting in a tyr275-to-cys (Y275C) substitution that was found in compound heterozygous state in a patient with leukoencephalopathy with vanishing white matter (VWM1; 603896) by Maletkovic et al. (2008), see 606686.0005. (less)
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001469118.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Leukodystrophy Due to eIF2B Mutations in Adults. | Shivaram S | The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques | 2022 | PMID: 34663487 |
Mutational analysis of the alpha subunit of eIF2B provides insights into the role of eIF2B bodies in translational control and VWM disease. | Norris K | The Journal of biological chemistry | 2021 | PMID: 33334879 |
X-Linked Thrombocytopenia and Vanishing White Matter Disease in a Child: Double Tragedy. | Pilania RK | Journal of clinical immunology | 2020 | PMID: 32865661 |
De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction. | De Franco E | Diabetes | 2020 | PMID: 31882561 |
Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (eIF) 2B associated with Vanishing White Matter disease. | Wortham NC | BMC medical genetics | 2015 | PMID: 26285592 |
Genetic and clinical heterogeneity in eIF2B-related disorder. | Maletkovic J | Journal of child neurology | 2008 | PMID: 18263758 |
Text-mined citations for rs758746181 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.