Submissions for variant NM_014239.4(EIF2B2):c.607_612delinsTG (p.Met203fs)

dbSNP: rs113994014

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627430	SCV000748429	pathogenic	not provided	2020-07-10	criteria provided, single submitter	clinical testing	Reported previously in association with vanishing white matter (VWM) disease in a patient who had a second variant in EIF2B2 (Leegwater et al., 2001); Previously reported in an adult female with ovarian failure and brain MRI anomalies similar to those seen in patients with VWM; this individual also had a second variant in EIF2B2 (Fogli et al., 2003); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11704758, 12707859, 31438897)
Illumina Laboratory Services, Illumina	RCV000779145	SCV000915651	pathogenic	Vanishing white matter disease	2018-10-18	criteria provided, single submitter	clinical testing	The EIF2B2 c.607_612delATGGCTinsTG (p.Met203TrpfsTer2) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Met203TrpfsTer2 variant has been reported in at least three studies in which it is found in a compound heterozygous state with a missense variant in at least three patients with childhood ataxia with central nervous system hypomyelination/vanishing white matter (Leegwater et al. 2001; Fogli et al. 2003; Ohlenbusch et al. 2005). The p.Met203TrpfsTer2 variant was absent from 700 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Li et al. (2004) performed functional studies in HEK293 cells, in which the p.Met203TrpfsTer2 variant protein was expressed with wild type versions of the other proteins involved in the EIF2B heteropentamer complex. SDS-PAGE and Western blotting for myc-tagged proteins showed that the p.Met203TrpfsTer2 variant was not able to form complexes with the other proteins suggesting that the C-terminal is needed for interaction and normal function. Based on the evidence and the potential impact of frameshift variants, the p.Met203TrpfsTer2 variant is considered pathogenic 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779145	SCV004021101	pathogenic	Vanishing white matter disease	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: EIF2B2 c.607_612delinsTG (p.Met203TrpfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251476 control chromosomes (gnomAD). c.607_612delinsTG has been reported in the literature in individuals affected with Leukoencephalopathy With Vanishing White Matter (e.g., Slynko_2020). These data indicate that the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 33432707). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000627430	SCV004535025	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met203Trpfs*2) in the EIF2B2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EIF2B2 are known to be pathogenic (PMID: 11704758, 12707859). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with leukoencephalopathy with vanishing white matter (PMID: 11704758). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV003221403	SCV000024762	pathogenic	Leukoencephalopathy with vanishing white matter 2	2003-06-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000779145	SCV000986729	not provided	Vanishing white matter disease		no assertion provided	phenotyping only	Variant interpretted as pathogenic and reported on 03/14/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.