Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV001139871 | SCV001300065 | uncertain significance | Vanishing white matter disease | 2018-01-15 | 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 |
RCV001856793 | SCV002196226 | uncertain significance | not provided | 2022-08-09 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 466 of the EIF2B4 protein (p.Arg466Gln). This variant is present in population databases (rs751555693, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with EIF2B4-related conditions. ClinVar contains an entry for this variant (Variation ID: 896911). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg466 amino acid residue in EIF2B4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18263758, 32180488; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, |
RCV003323799 | SCV004029147 | likely benign | not specified | 2023-07-26 | criteria provided, single submitter | clinical testing | Variant summary: EIF2B4 c.1397G>A (p.Arg466Gln) results in a conservative amino acid change in 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-05 in 251468 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in EIF2B4 causing Leukoencephalopathy With Vanishing White Matter phenotype (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1397G>A has been reported in the literature in at least one heterozygous individual affected with primary ovarian insufficiency, a clinical feature of EIF2B4-related conditions (e.g., Liu_2020). However, this report does not provide unequivocal conclusions about association of the variant with Leukoencephalopathy With Vanishing White Matter. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32962729). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |