Submissions for variant NM_014239.4(EIF2B2):c.890del (p.Phe297fs)

dbSNP: rs773041356

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779146	SCV000915653	uncertain significance	Vanishing white matter disease	2018-12-25	criteria provided, single submitter	clinical testing	This variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. This variant is located in the last exon or in the last 50 bp of the penultimate exon and may escape nonsense-mediated decay. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873180	SCV002109618	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe297Serfs*43) in the EIF2B2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the EIF2B2 protein. This variant is present in population databases (rs773041356, gnomAD 0.03%). 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: 632220). This variant disrupts a region of the EIF2B2 protein in which other variant(s) (p.Val316Asp) have been determined to be pathogenic (PMID: 11704758, 33432707). 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.