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

gnomAD frequency: 0.00006  dbSNP: rs113994006

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255352	SCV000321594	uncertain significance	not provided	2021-04-22	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 11835386)
Illumina Laboratory Services, Illumina	RCV000004339	SCV000376813	uncertain significance	Vanishing white matter disease	2017-04-28	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV003492283	SCV002024474	likely pathogenic	Leukoencephalopathy with vanishing white matter 1	2021-08-24	criteria provided, single submitter	clinical testing
Invitae	RCV000255352	SCV003272364	likely pathogenic	not provided	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the EIF2B1 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), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in EIF2B1 cause disease. This variant is present in population databases (rs113994006, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with leukoencephalopathy with vanishing white matter (PMID: 11835386). This variant is also known as IVS2+1G>A. ClinVar contains an entry for this variant (Variation ID: 4123). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004339	SCV004029308	likely pathogenic	Vanishing white matter disease	2023-07-21	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000004339	SCV000024510	pathogenic	Vanishing white matter disease	2002-02-01	no assertion criteria provided	literature only