ClinVar Genomic variation as it relates to human health
NM_003907.3(EIF2B5):c.806G>A (p.Arg269Gln)
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_003907.3(EIF2B5):c.806G>A (p.Arg269Gln)
Variation ID: 942204 Accession: VCV000942204.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q27.1 3: 184140120 (GRCh38) [ NCBI UCSC ] 3: 183857908 (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 Jul 16, 2020 Jul 7, 2024 Mar 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003907.3:c.806G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003898.2:p.Arg269Gln missense NC_000003.12:g.184140120G>A NC_000003.11:g.183857908G>A NG_015826.1:g.10099G>A LRG_1278:g.10099G>A LRG_1278t1:c.806G>A LRG_1278p1:p.Arg269Gln - Protein change
- R269Q
- Other names
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- Canonical SPDI
- NC_000003.12:184140119: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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
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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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EIF2B5 | - | - |
GRCh38 GRCh37 |
675 | 764 |
Conditions - Germline
Condition
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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
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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, multiple submitters, no conflicts
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Feb 14, 2023 | RCV001212143.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 11, 2024 | RCV002471047.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV003389333.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2024 | RCV004526089.1 |
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
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
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447596.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Leukodystrophy (present)
Sex: female
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Pathogenic
(May 06, 2021)
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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: SCV002768862.1
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). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygotes, 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) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes to glycine and leucine at this residue have been described in affected patients (PMID:15776425, 15136673). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Multiple affected individuals have been reported with this variant in a homozygous or compound heterozygous state (PMID:16864840, 19158808, 25761052, 29933199, 27779215). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (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
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004101485.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The EIF2B5 c.806G>A p.Arg269Gln variant has been reported in individuals affected with vanishing white matter disease (Federico A et al, 2006). This variant disrupts the … (more)
The EIF2B5 c.806G>A p.Arg269Gln variant has been reported in individuals affected with vanishing white matter disease (Federico A et al, 2006). This variant disrupts the p.Arg269 amino acid residue in EIF2B5. Other variant(s) that disrupt this residue have been observed in individuals with EIF2B5-related conditions (Fogli et al, 2004), which suggests that this may be a clinically significant amino acid residue. This variant is reported with the allele frequency (0.00039%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Arg at position 269 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Arg269Gln in EIF2B5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Neurodegeneration (present) , Cerebellar ataxia (present) , Seizure (present)
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Pathogenic
(Feb 14, 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: SCV001383719.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 269 of the EIF2B5 protein (p.Arg269Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 269 of the EIF2B5 protein (p.Arg269Gln). This variant is present in population databases (rs113994057, gnomAD 0.0009%). This missense change has been observed in individuals with vanishing white matter disease (PMID: 16864840, 19158808, 27779215, 29933199). ClinVar contains an entry for this variant (Variation ID: 942204). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant disrupts the p.Arg269 amino acid residue in EIF2B5. Other variant(s) that disrupt this residue have been observed in individuals with EIF2B5-related conditions (PMID: 15136673, 15776425), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039569.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
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Pathogenic
(Mar 11, 2024)
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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: SCV005062094.2
First in ClinVar: Jun 29, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: EIF2B5 c.806G>A (p.Arg269Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: EIF2B5 c.806G>A (p.Arg269Gln) results in a conservative amino acid change in 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 4e-06 in 251456 control chromosomes (gnomAD). c.806G>A has been reported in the literature in multiple individuals affected with Leukoencephalopathy With Vanishing White Matter (examples: Zhang_2015, Federico_2006, and Ren_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25761052, 35389136, 16864840). ClinVar contains an entry for this variant (Variation ID: 942204). Based on the evidence outlined above, the variant was classified as pathogenic. (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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Genotypic and phenotypic characteristics of juvenile/adult onset vanishing white matter: a series of 14 Chinese patients. | Ren Y | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2022 | PMID: 35389136 |
Vanishing white matter disease with a novel EIF2B5 mutation: A 10-year follow-up. | Bektaş G | Clinical neurology and neurosurgery | 2018 | PMID: 29933199 |
The use of targeted genomic capture and massively parallel sequencing in diagnosis of Chinese Leukoencephalopathies. | Wang X | Scientific reports | 2016 | PMID: 27779215 |
Fifteen novel EIF2B1-5 mutations identified in Chinese children with leukoencephalopathy with vanishing white matter and a long term follow-up. | Zhang H | PloS one | 2015 | PMID: 25761052 |
Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease. | Wu Y | Journal of human genetics | 2009 | PMID: 19158808 |
Peripheral neuropathy in vanishing white matter disease with a novel EIF2B5 mutation. | Federico A | Neurology | 2006 | PMID: 16864840 |
Identification of ten novel mutations in patients with eIF2B-related disorders. | Ohlenbusch A | Human mutation | 2005 | PMID: 15776425 |
The effect of genotype on the natural history of eIF2B-related leukodystrophies. | Fogli A | Neurology | 2004 | PMID: 15136673 |
Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. | Leegwater PA | Nature genetics | 2001 | PMID: 11704758 |
Text-mined citations for rs113994057 ...
HelpRecord last updated Jul 15, 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.