Submissions for variant NM_003907.3(EIF2B5):c.1832C>T (p.Pro611Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002913196	SCV003249749	uncertain significance	not provided	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 611 of the EIF2B5 protein (p.Pro611Leu). This variant is present in population databases (rs374710986, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with EIF2B5-related conditions. 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 EIF2B5 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV003340549	SCV004047219	uncertain significance	Leukoencephalopathy with vanishing white matter 1		criteria provided, single submitter	clinical testing	The missense variant in c.1832C>T (p.Pro611Leu) in EIF2B5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Pro611Leu variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.003536% in gnomAD database. This variant has not been reported to the ClinVar database. The amino acid Pro at position 611 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Pro611Leu in EIF2B5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS).
Ambry Genetics	RCV004617106	SCV005119479	uncertain significance	Inborn genetic diseases	2024-05-14	criteria provided, single submitter	clinical testing	The c.1832C>T (p.P611L) alteration is located in exon 13 (coding exon 13) of the EIF2B5 gene. This alteration results from a C to T substitution at nucleotide position 1832, causing the proline (P) at amino acid position 611 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.