ClinVar Genomic variation as it relates to human health
NM_001034116.2(EIF2B4):c.1399C>T (p.Arg467Trp)
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.
Likely pathogenic(2); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001034116.2(EIF2B4):c.1399C>T (p.Arg467Trp)
Variation ID: 287459 Accession: VCV000287459.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 27364573 (GRCh38) [ NCBI UCSC ] 2: 27587440 (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 Dec 6, 2016 Feb 14, 2024 Jun 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001034116.2:c.1399C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001029288.1:p.Arg467Trp missense NM_001318965.2:c.1462C>T NP_001305894.1:p.Arg488Trp missense NM_001318966.2:c.1354C>T NP_001305895.1:p.Arg452Trp missense NM_001318967.2:c.1306C>T NP_001305896.1:p.Arg436Trp missense NM_001318968.2:c.814C>T NP_001305897.1:p.Arg272Trp missense NM_001318969.2:c.781C>T NP_001305898.1:p.Arg261Trp missense NM_015636.4:c.1396C>T NP_056451.3:p.Arg466Trp missense NM_172195.4:c.1459C>T NP_751945.2:p.Arg487Trp missense NC_000002.12:g.27364573G>A NC_000002.11:g.27587440G>A NG_009305.1:g.10885C>T - Protein change
- R466W, R467W, R272W, R436W, R487W, R488W, R261W, R452W
- Other names
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- Canonical SPDI
- NC_000002.12:27364572: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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
Help
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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EIF2B4 | - | - |
GRCh38 GRCh37 |
215 | 447 | |
GTF3C2-AS2 | - | - | - | GRCh38 | - | 220 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 12, 2023 | RCV000339634.8 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 23, 2023 | RCV000765662.7 |
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
Help
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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Uncertain significance
(Apr 21, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000341239.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 3
Sex: mixed
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy with vanishing white matter 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000896996.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(-)
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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:
inherited
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001479314.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
Sex: male
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Likely pathogenic
(Feb 23, 2023)
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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:
unknown
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3billion
Accession: SCV003841530.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
This homozygous variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Missense changes are a common disease-causing … (more)
This homozygous variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.47). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with EIF2B4-related disorder (PMID: 18263758). A different missense change at the same codon (p.Arg467Gln) has been reported to be associated with EIF2B4-related disorder (PMID: 32962729). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present)
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Likely pathogenic
(Jun 12, 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: SCV002271358.3
First in ClinVar: Mar 28, 2022 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 EIF2B4 function (PMID: 27812215). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 287459). This variant is also known as p.R467W or p.R487W. This missense change has been observed in individual(s) with EIF2B4-related conditions (PMID: 18263758, 32180488, 34745209; Invitae). 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 (rs138249238, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 466 of the EIF2B4 protein (p.Arg466Trp). (less)
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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
HelpTitle | Author | Journal | Year | Link |
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Correlation Between Genotype and Age of Onset in Leukoencephalopathy With Vanishing White Matter. | Deng J | Frontiers in genetics | 2021 | PMID: 34745209 |
Whole-exome sequencing in patients with premature ovarian insufficiency: early detection and early intervention. | Liu H | Journal of ovarian research | 2020 | PMID: 32962729 |
Leukodystrophies and Genetic Leukoencephalopathies in Children Specified by Exome Sequencing in an Expanded Gene Panel. | Parayil Sankaran B | Journal of child neurology | 2020 | PMID: 32180488 |
Paradoxical Sensitivity to an Integrated Stress Response Blocking Mutation in Vanishing White Matter Cells. | Sekine Y | PloS one | 2016 | PMID: 27812215 |
Genetic and clinical heterogeneity in eIF2B-related disorder. | Maletkovic J | Journal of child neurology | 2008 | PMID: 18263758 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EIF2B4 | - | - | - | - |
Text-mined citations for rs138249238 ...
HelpRecord last updated Feb 20, 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.