Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001851695 | SCV002284229 | likely pathogenic | not provided | 2021-05-16 | 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. This sequence change replaces phenylalanine with valine at codon 56 of the EIF2B5 protein (p.Phe56Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with EIF2B5-related conditions (PMID: 15136673). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5951). 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 expected to disrupt EIF2B5 protein function. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004700193 | SCV005204668 | uncertain significance | not specified | 2024-06-19 | criteria provided, single submitter | clinical testing | Variant summary: EIF2B5 c.166T>G (p.Phe56Val) results in a non-conservative amino acid change located in the translation initiation factor eIF-2B subunit epsilon, N-terminal domain (IPR035543) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-06 in 208642 control chromosomes (gnomAD). c.166T>G has been reported in the literature in two siblings affected with severe, infantile-onset central hypomyelination syndrome or vanishing white matter disease (Fogli_2004, Passemard_2007). These data indicate that the variant may be associated with disease. In vitro and in vivo functional assays shows reduced activity for the variant. The following publications have been ascertained in the context of this evaluation (PMID: 23335982, 15054402, 17646634, 21560189). ClinVar contains an entry for this variant (Variation ID: 5951). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Fulgent Genetics, |
RCV003221417 | SCV005661978 | likely pathogenic | Leukoencephalopathy with vanishing white matter 5 | 2024-06-19 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV003221417 | SCV000026497 | pathogenic | Leukoencephalopathy with vanishing white matter 5 | 2007-07-24 | no assertion criteria provided | literature only |