Submissions for variant NM_020365.5(EIF2B3):c.687T>G (p.Ile229Met)

gnomAD frequency: 0.00001  dbSNP: rs538917969

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	RCV002254404	SCV002525548	likely pathogenic	Vanishing white matter disease	2022-05-12	criteria provided, single submitter	clinical testing	The c.687T>G variant is not present in publicly available population databases like Exome Variant Server (EVS). The heterozygous state of the variant is present in 1000 Genomes, Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and Indian Exome Database. The variant is not present in our in-house exome database. The variant was previously identified in similarly affected patients (PMID: 16807905, 18263758, 19909266) and reported to Human Genome Mutation Database (HGMD ID: CM066788). In-silico pathogenicity prediction programs like SIFT, PolyPhen-2. MutationTaster2, CADD etc. predicted this variant to be likely deleterious.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155473	SCV003844288	uncertain significance	not specified	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: EIF2B3 c.687T>G (p.Ile229Met) 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 8.7e-05 in 251450 control chromosomes, predominantly at a frequency of 0.00046 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in EIF2B3 causing Leukoencephalopathy With Vanishing White Matter phenotype (0.00032), suggesting that the variant may be a benign polymorphism found primarily in populations of South Asian origin. c.687T>G has been reported in the literature in individuals affected with Leukoencephalopathy With Vanishing White Matter, in multiple cases without a second allele reported or with a second allele that is unknown signficance (Pronk_2006, Maletkovic_2008, Sankaran_2020). In one patient the variant was reported in the homozygous state (Slynko_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS.
Neuberg Centre For Genomic Medicine, NCGM	RCV004584967	SCV005073959	likely pathogenic	Leukoencephalopathy with vanishing white matter 1		criteria provided, single submitter	clinical testing	The observed missense c.687T>G(p.Ile229Met) variant in EIF2B3 gene has been reported in compound heterozygous or homozygous state in individuals affected with EIF2B3 related disease (Pavitt GD, et. al., 2009; Parayil Sankaran B, et. al.,2020; Slynko I, et.al., 2021). This variant is present with an allele frequency of 0.008% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance/ Likely pathogenic. The amino acid change p.Ile229Met in EIF2B3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ile at position 229 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic.