ClinVar Genomic variation as it relates to human health
NM_020365.5(EIF2B3):c.260C>T (p.Ala87Val)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020365.5(EIF2B3):c.260C>T (p.Ala87Val)
Variation ID: 4439 Accession: VCV000004439.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 44978349 (GRCh38) [ NCBI UCSC ] 1: 45444021 (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 Nov 9, 2018 Oct 8, 2024 Jan 29, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020365.5:c.260C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065098.1:p.Ala87Val missense NM_001166588.3:c.260C>T NP_001160060.1:p.Ala87Val missense NM_001261418.2:c.260C>T NP_001248347.1:p.Ala87Val missense NC_000001.11:g.44978349G>A NC_000001.10:g.45444021G>A NG_015864.1:g.13341C>T Q9NR50:p.Ala87Val - Protein change
- A87V
- Other names
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- Canonical SPDI
- NC_000001.11:44978348:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD) 0.00012
- Links
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
Help
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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| EIF2B3 | - | - |
GRCh38 GRCh37 |
300 | 320 | |
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 (2) |
criteria provided, single submitter
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Mar 22, 2023 | RCV000004689.13 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV001377725.12 | |
| Pathogenic (1) |
no assertion criteria provided
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Feb 1, 2002 | RCV003221406.3 | |
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EIF2B3-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Jan 18, 2024 | RCV003914806.2 |
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
Help
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
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
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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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Pathogenic
(Mar 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Vanishing white matter disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003923145.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: EIF2B3 c.260C>T (p.Ala87Val) results in a non-conservative amino acid change located in the Nucleotidyl transferase domain (IPR005835) of the encoded protein sequence. Four … (more)
Variant summary: EIF2B3 c.260C>T (p.Ala87Val) results in a non-conservative amino acid change located in the Nucleotidyl transferase domain (IPR005835) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251402 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EIF2B3 causing Leukoencephalopathy With Vanishing White Matter (8.8e-05 vs 0.00032), allowing no conclusion about variant significance. c.260C>T has been reported in the literature in multiple individuals affected with Leukoencephalopathy With Vanishing White Matter and related clinical features (Example: Robinson_2014, van der Knapp_2002, Cohen_2020, LaPiana_2012 etc.) . These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as Pathogenic (n=1), Likely Pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 29, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001575125.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 87 of the EIF2B3 protein (p.Ala87Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 87 of the EIF2B3 protein (p.Ala87Val). This variant is present in population databases (rs113994022, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of leukoencephalopathy with vanishing white matter (PMID: 11835386, 22312164, 25079571, 31418856). ClinVar contains an entry for this variant (Variation ID: 4439). 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 EIF2B3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EIF2B3 function (PMID: 33517449). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001783581.4
First in ClinVar: Aug 14, 2021 Last updated: Mar 26, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27864579, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27864579, 31418856, 11835386, 25079571, 22312164, 23115207, 16998732, 14572143, 26162493, 31589614, 33084218, 27535533, 35783294) (less)
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Pathogenic
(Feb 01, 2002)
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no assertion criteria provided
Method: literature only
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LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024864.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 17, 2023 |
Comment on evidence:
In a patient (vwm47) with leukoencephalopathy with vanishing white matter (VWM3; 620313), van der Knaap et al. (2002) found homozygosity for an ala87-to-val (A87V) substitution … (more)
In a patient (vwm47) with leukoencephalopathy with vanishing white matter (VWM3; 620313), van der Knaap et al. (2002) found homozygosity for an ala87-to-val (A87V) substitution in the EIF2B3 gene, which resulted from a C-to-T transition at nucleotide 362 (c.362C-T) in exon 2. Ghezzi et al. (2012) identified homozygosity for an A87V mutation in a 66-year-old woman with adult-onset VWM disease and a history of premature ovarian failure at 24 years. She had a 5-year history of progressive gait impairment and behavioral and cognitive disturbances and had experienced a rapid worsening of her clinical condition 10 days prior to evaluation. (less)
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Pathogenic
(Jan 18, 2024)
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no assertion criteria provided
Method: clinical testing
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EIF2B3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004733499.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The EIF2B3 c.260C>T variant is predicted to result in the amino acid substitution p.Ala87Val. This variant was reported in homozygous and compound heterozygous state in … (more)
The EIF2B3 c.260C>T variant is predicted to result in the amino acid substitution p.Ala87Val. This variant was reported in homozygous and compound heterozygous state in multiple individuals with leukoencephalopathy with vanishing white matter (van der Knaap et al. 2002. PubMed ID: 11835386; La Piana et al. 2012. PubMed ID: 22312164; Ghezzi et al. 2012. PubMed ID: 23115207; Robinson et al. 2014. PubMed ID: 25079571; Cohen et al. 2019. PubMed ID: 31418856; Capalbo et al. 2019. PubMed ID: 31589614 Table S1; Salinas et al. 2020. PubMed ID: 33084218 Table S1). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Vanishing white matter disease
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000996321.2
First in ClinVar: Nov 02, 2019 Last updated: Oct 01, 2022 |
Comment:
French-Canadian (non-Cree) founder variant
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Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish. | Lee YR | Human molecular genetics | 2021 | PMID: 33517449 |
| Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years. | Cohen L | Annals of human genetics | 2020 | PMID: 31418856 |
| Vanishing white matter disease in French-Canadian patients from Quebec. | Robinson MÈ | Pediatric neurology | 2014 | PMID: 25079571 |
| A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation. | Ghezzi L | Neurology | 2012 | PMID: 23115207 |
| Adult-onset vanishing white matter disease due to a novel EIF2B3 mutation. | La Piana R | Archives of neurology | 2012 | PMID: 22312164 |
| Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. | van der Knaap MS | Annals of neurology | 2002 | PMID: 11835386 |
Text-mined citations for rs113994022 ...
HelpRecord last updated Oct 13, 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.