ClinVar Genomic variation as it relates to human health
NM_001034116.2(EIF2B4):c.728C>T (p.Pro243Leu)
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_001034116.2(EIF2B4):c.728C>T (p.Pro243Leu)
Variation ID: 420062 Accession: VCV000420062.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 27367800 (GRCh38) [ NCBI UCSC ] 2: 27590667 (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 Apr 27, 2017 Feb 14, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001034116.2:c.728C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001029288.1:p.Pro243Leu missense NM_001318965.2:c.791C>T NP_001305894.1:p.Pro264Leu missense NM_001318966.2:c.683C>T NP_001305895.1:p.Pro228Leu missense NM_001318967.2:c.635C>T NP_001305896.1:p.Pro212Leu missense NM_001318968.2:c.143C>T NP_001305897.1:p.Pro48Leu missense NM_001318969.2:c.110C>T NP_001305898.1:p.Pro37Leu missense NM_015636.4:c.725C>T NP_056451.3:p.Pro242Leu missense NM_172195.4:c.788C>T NP_751945.2:p.Pro263Leu missense NC_000002.12:g.27367800G>A NC_000002.11:g.27590667G>A NG_009305.1:g.7658C>T - Protein change
- P242L, P243L, P264L, P48L, P212L, P37L, P228L, P263L
- Other names
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- Canonical SPDI
- NC_000002.12:27367799: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) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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
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
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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
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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000482195.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 22, 2022 | RCV001782965.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 12, 2019 | RCV003492070.2 |
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
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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
(Mar 06, 2017)
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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: SCV000568545.3
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
The P242L variant in the EIF2B4 gene has been reported previously, using alternate nomenclature P243L, in individuals with leukodystrophy with vanishing white matter when present … (more)
The P242L variant in the EIF2B4 gene has been reported previously, using alternate nomenclature P243L, in individuals with leukodystrophy with vanishing white matter when present in the homozygous state (Fogli et al., 2004). The P242L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P242L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The P242L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
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Pathogenic
(Jun 24, 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: SCV002557338.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 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 reported 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 reported 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) 0115 - Variants in this gene are known to have variable expressivity (PMIDs: 16998732, 35389136). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 6 heterozygotes, 0 homozygotes). (SP) 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 initiation factor 2 subunit domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It was regarded as likely pathogenic in ClinVar and detected in multiple homozygous and compound heterozygous individuals with leukodystrophy (PMIDs: 15136673, 32071834). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Patient’s EBV-transformed lymphocytes presented a decrease to 45 to 80% of elF2B GEF activity (PMID: 20016818). (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_001034116.1(EIF2B4):c.631G>T; p.(Gly211Cys)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Sep 22, 2022)
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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: SCV002598902.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: EIF2B4 c.725C>T (p.Pro242Leu) 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: EIF2B4 c.725C>T (p.Pro242Leu) 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 2e-05 in 251478 control chromosomes. c.725C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with features of Leukoencephalopathy With Vanishing White Matter (example, Maletkovic_2008, Horzinski_2009, Slynko_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in approximately 54% of normal eIF2B GEF activity in transformed lymphocytes from a homozygous individual (Horzinski_2009) when the activity threshold was set at </=77.5%. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Mar 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy with vanishing white matter 4
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024475.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jan 27, 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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Invitae
Accession: SCV003523971.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 242 of the EIF2B4 protein (p.Pro242Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 242 of the EIF2B4 protein (p.Pro242Leu). This variant is present in population databases (rs113994030, gnomAD 0.004%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 15136673, 32071834). This variant is also known as p.Pro243Leu and c.791C>T (p.Pro264Leu). ClinVar contains an entry for this variant (Variation ID: 420062). 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. 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. (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: Eukaryotic initiation factor 2B model and the impact of missense mutations. | Slynko I | Molecular genetics & genomic medicine | 2021 | PMID: 33432707 |
Hyperinsulinaemic hypoglycaemia: A rare association of vanishing white matter disease. | Bursle C | JIMD reports | 2019 | PMID: 32071834 |
Eukaryotic initiation factor 2B (eIF2B) GEF activity as a diagnostic tool for EIF2B-related disorders. | Horzinski L | PloS one | 2009 | PMID: 20016818 |
Genetic and clinical heterogeneity in eIF2B-related disorder. | Maletkovic J | Journal of child neurology | 2008 | PMID: 18263758 |
The spectrum of mutations for the diagnosis of vanishing white matter disease. | Scali O | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2006 | PMID: 16998732 |
Screening for known mutations in EIF2B genes in a large panel of patients with premature ovarian failure. | Fogli A | BMC women's health | 2004 | PMID: 15507143 |
The effect of genotype on the natural history of eIF2B-related leukodystrophies. | Fogli A | Neurology | 2004 | PMID: 15136673 |
Text-mined citations for rs113994030 ...
HelpRecord last updated Mar 17, 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.