NM_014239.4(EIF2B2):c.285-1G>A AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001572007.5

Allele description [Variation Report for NM_014239.4(EIF2B2):c.285-1G>A]

NM_014239.4(EIF2B2):c.285-1G>A

Gene:

EIF2B2:eukaryotic translation initiation factor 2B subunit beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q24.3

Genomic location:

Preferred name:

NM_014239.4(EIF2B2):c.285-1G>A

HGVS:

NC_000014.9:g.75003550G>A
NG_013333.1:g.5642G>A
NG_013333.2:g.5631G>A
NM_014239.3:c.285-1G>A
NM_014239.4:c.285-1G>AMANE SELECT
NC_000014.8:g.75470253G>A

Links:

dbSNP: rs373906805

NCBI 1000 Genomes Browser:

rs373906805

Molecular consequence:

NM_014239.4:c.285-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001796578	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Oct 17, 2019)	germline	clinical testing	Citation Link,
SCV004277442	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 11704758, 12707859, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001796578

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Oct 17, 2019)

germline

clinical testing

Citation Link,

SCV004277442

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.

Leegwater PA, Vermeulen G, Könst AA, Naidu S, Mulders J, Visser A, Kersbergen P, Mobach D, Fonds D, van Berkel CG, Lemmers RJ, Frants RR, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS.

Nat Genet. 2001 Dec;29(4):383-8.

PubMed [citation]

PMID:: 11704758

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV001796578.1

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

Description

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004277442.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change affects an acceptor splice site in intron 2 of the EIF2B2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EIF2B2 are known to be pathogenic (PMID: 11704758, 12707859). This variant is present in population databases (rs373906805, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with EIF2B2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1205361). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

#	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: Sep 29, 2024

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