Submissions for variant NM_020365.5(EIF2B3):c.130G>A (p.Glu44Lys)

gnomAD frequency: 0.00001  dbSNP: rs201162647

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000296409	SCV000357867	uncertain significance	Vanishing white matter disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850561	SCV002218644	uncertain significance	not provided	2021-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 44 of the EIF2B3 protein (p.Glu44Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs201162647, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with EIF2B3-related conditions. ClinVar contains an entry for this variant (Variation ID: 297449). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526661	SCV005039808	uncertain significance	not specified	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: EIF2B3 c.130G>A (p.Glu44Lys) results in a conservative amino acid change located in the Nucleotidyl transferase domain (IPR005835) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251480 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.130G>A has been reported in the literature in the compound heterozygous state in individuals affected with Leukoencephalopathy With Vanishing White Matter (e.g. Xu_2022, Dong_2023), as well as in an unaffected sibling of one proband. Since the penetrance of Leukoencephalopathy With Vanishing White Matter (0.67) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34755279, 36380532, 37981684). ClinVar contains an entry for this variant (Variation ID: 297449). Based on the evidence outlined above, the variant was classified as uncertain significance.