ClinVar Miner

Submissions for variant NM_001034116.2(EIF2B4):c.1399C>T (p.Arg467Trp)

gnomAD frequency: 0.00004  dbSNP: rs138249238
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000339634 SCV000341239 uncertain significance not provided 2016-04-21 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000765662 SCV000896996 uncertain significance Vanishing white matter disease 2018-10-31 criteria provided, single submitter clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV000765662 SCV001479314 uncertain significance Vanishing white matter disease criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000339634 SCV002271358 likely pathogenic not provided 2023-06-12 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects EIF2B4 function (PMID: 27812215). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 287459). This variant is also known as p.R467W or p.R487W. This missense change has been observed in individual(s) with EIF2B4-related conditions (PMID: 18263758, 32180488, 34745209; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs138249238, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 466 of the EIF2B4 protein (p.Arg466Trp).
3billion RCV000765662 SCV003841530 likely pathogenic Vanishing white matter disease 2023-02-23 criteria provided, single submitter clinical testing This homozygous variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.47). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with EIF2B4-related disorder (PMID: 18263758). A different missense change at the same codon (p.Arg467Gln) has been reported to be associated with EIF2B4-related disorder (PMID: 32962729). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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