NM_001414.4(EIF2B1):c.252+1G>A AND Vanishing white matter disease

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 21, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000004339.14

Allele description [Variation Report for NM_001414.4(EIF2B1):c.252+1G>A]

NM_001414.4(EIF2B1):c.252+1G>A

Gene:

EIF2B1:eukaryotic translation initiation factor 2B subunit alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.31

Genomic location:

Preferred name:

NM_001414.4(EIF2B1):c.252+1G>A

HGVS:

NC_000012.12:g.123630396C>T
NG_015862.1:g.8381G>A
NG_015862.2:g.8290G>A
NM_001414.4:c.252+1G>AMANE SELECT
NC_000012.11:g.124114943C>T
NM_001414.3:c.252+1G>A

Nucleotide change:

IVS2DS, G-A, +1

Links:

OMIM: 606686.0001; dbSNP: rs113994006

NCBI 1000 Genomes Browser:

rs113994006

Molecular consequence:

NM_001414.4:c.252+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Vanishing white matter disease
Synonyms:: CACH syndrome; Childhood ataxia with diffuse central nervous system hypomyelination; Leukoencephalopathy with vanishing white matter; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0800448; MedGen: C1858991; Orphanet: 99853; OMIM: PS603896

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024510	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000376813	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004029308	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 21, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000024510

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2002)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000376813

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Apr 28, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV004029308

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jul 21, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.

van der Knaap MS, Leegwater PA, Könst AA, Visser A, Naidu S, Oudejans CB, Schutgens RB, Pronk JC.

Ann Neurol. 2002 Feb;51(2):264-70.

PubMed [citation]

PMID:: 11835386

Details of each submission

From OMIM, SCV000024510.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with leukoencephalopathy with vanishing white matter (VWM1; 603896), van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B1 gene: IVS2+1G-A and a 622A-T transversion in exon 6, causing an asn208-to-tyr (N208Y) missense change in the polypeptide (606686.0002).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000376813.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The EIF2B1 c.252+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.252+1G>A variant has been reported in one study in which it was found in one patient with childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), in a compound heterozygous state with another missense variant (van der Knaap et al. 2001). The c.252+1G>A variant was absent from 120 control chromosomes but is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. Based on the potential impact of splice donor variants and limited evidence, the c.252+1G>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for childhood ataxia with central nervous system hypomyelination/vanishing white matter. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004029308.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: EIF2B1 c.252+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251368 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EIF2B1 causing Leukoencephalopathy With Vanishing White Matter (6e-05 vs 0.00016), allowing no conclusion about variant significance. c.252+1G>A has been reported in the literature in individuals affected with Leukoencephalopathy With Vanishing White Matter (van der Knaap_2002). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 11835386). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely pathogenic (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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