Submissions for variant NM_003907.3(EIF2B5):c.318A>T (p.Leu106Phe)

gnomAD frequency: 0.00002  dbSNP: rs113994048

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724783	SCV000227299	pathogenic	not provided	2015-04-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624816	SCV000742829	pathogenic	Inborn genetic diseases	2017-10-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000175759	SCV000807242	pathogenic	Vanishing white matter disease		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724783	SCV001584885	pathogenic	not provided	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 106 of the EIF2B5 protein (p.Leu106Phe). This variant is present in population databases (rs113994048, gnomAD 0.03%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 11704758, 25089094, 31418856). ClinVar contains an entry for this variant (Variation ID: 195203). 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 tolerated. Experimental studies have shown that this missense change affects EIF2B5 function (PMID: 14993275). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000724783	SCV001791911	pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	Reported with a second EIF2B5 variant, phase unknown, in patients with vanishing white matter disease in published literature (Leegwater et al., 2001; Turon-Vinas et al., 2014; Slynko et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In addition, in silico splice predictors suggest this variant may lead to abnormal gene splicing; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29382480, 12707859, 31418856, 9710032, 18263758, 14572143, 16998732, 16807905, 20838246, 25089094, 33084218, 28252636, 35012964, 33432707, 11704758)
Neuberg Centre For Genomic Medicine, NCGM	RCV004576925	SCV005061002	pathogenic	Leukoencephalopathy with vanishing white matter 1		criteria provided, single submitter	clinical testing	The missense variant c.318A>T (p.Leu106Phe) in the EIF2B5 gene has been reported previously in heterozygous and homozygous states in multiple individuals affected with Vanishing white matter leukoencephalopathy. Experimental studies have shown that this missense change affects the EIF2B5 function (Turón-Viñas et al., 2014; Richardson et al., 2004). However there is no recent literature supporting experimental evidence. This variant is reported with the allele frequency (0.004%) in the gnomAD. It is submitted to ClinVar with varying interpretations as Pathogenic/ Likely Pathogenic. The amino acid Leucine at position 106 is changed to a Phenylalanine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004755790	SCV005360791	pathogenic	EIF2B5-related disorder	2024-08-21	no assertion criteria provided	clinical testing	The EIF2B5 c.318A>T variant is predicted to result in the amino acid substitution p.Leu106Phe. This variant has been reported in homozygous and compound heterozygous states individuals with features consistent with leukoencephalopathy with vanishing white matter (Supplementary Table 2, Cohen et al. 2019. PubMed ID: 31418856; Esmer et al. 2017. PubMed ID: 29382480; Supplementary Table 1, Salinas et al. 2020. PubMed ID: 33084218; eTable 2, Schlüter et al. 2022. PubMed ID: 35012964; Supplementary Table 1, phasing unknown in Baldridge et al. 2017. PubMed ID: 28252636; phasing unknown in Leegwater et al. 2001. PubMed ID: 11704758). This variant is reported in 0.032% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.