Submissions for variant NM_001414.4(EIF2B1):c.770_771del (p.Leu257fs)

dbSNP: rs746435041

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002238600	SCV002511631	uncertain significance	not specified	2022-04-07	criteria provided, single submitter	clinical testing	Variant summary: EIF2B1 c.770_771delTC (p.Leu257GlnfsX42) located in the last exon 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 allele was found at a frequency of 1.6e-05 in 251410 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.770_771delTC in individuals affected with Leukoencephalopathy With Vanishing White Matter and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003688952	SCV004449694	pathogenic	not provided	2023-07-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu257Glnfs*42) in the EIF2B1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the EIF2B1 protein. This variant is present in population databases (rs746435041, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with EIF2B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1683289). This variant disrupts a region of the EIF2B1 protein in which other variant(s) (p.Try275Cys) have been determined to be pathogenic (PMID: 18263758, 32865661, 33334879). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.