Submissions for variant NM_020365.5(EIF2B3):c.134G>A (p.Arg45His)

gnomAD frequency: 0.00014  dbSNP: rs139445917

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001100679	SCV001257209	uncertain significance	Vanishing white matter disease	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856367	SCV002183087	uncertain significance	not provided	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 45 of the EIF2B3 protein (p.Arg45His). This variant is present in population databases (rs139445917, gnomAD 0.05%). This missense change has been observed in individual(s) with infantile encephalopathy with epilepsy and dysmorphic corpus callosum (PMID: 23932106). ClinVar contains an entry for this variant (Variation ID: 876174). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EIF2B3 protein function. 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.
Ambry Genetics	RCV002556033	SCV003747514	uncertain significance	Inborn genetic diseases	2022-08-24	criteria provided, single submitter	clinical testing	The c.134G>A (p.R45H) alteration is located in exon 2 (coding exon 1) of the EIF2B3 gene. This alteration results from a G to A substitution at nucleotide position 134, causing the arginine (R) at amino acid position 45 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV003446627	SCV004171918	uncertain significance	Leukoencephalopathy with vanishing white matter 3		criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001856367	SCV005186667	uncertain significance	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV004758143	SCV005349241	uncertain significance	EIF2B3-related disorder	2024-07-02	no assertion criteria provided	clinical testing	The EIF2B3 c.134G>A variant is predicted to result in the amino acid substitution p.Arg45His. This variant was reported in the homozygous state in an individual with early-onset epileptic encephalopathy and was interpreted as a variant of uncertain significance (Basel-Vanagaite et al. 2013. PubMed ID: 23932106). This variant was also reported in the heterozygous state in an individual with premature ovarian failure (Turkyilmaz et al. 2022. PubMed ID: 35066699). This variant is reported in 0.046% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.