Submissions for variant NM_020964.3(EPG5):c.713G>T (p.Arg238Leu)

gnomAD frequency: 0.00001  dbSNP: rs370270531

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027782	SCV001190389	uncertain significance	Vici syndrome	2021-03-30	criteria provided, single submitter	clinical testing	EPG5 NM_020964.2 exon 2 p.Arg238Leu (c.713G>T): This variant has not been reported in the literature and is present in 0.001% (2/113172) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/18-43534655-C-A). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001027782	SCV001201546	uncertain significance	Vici syndrome	2021-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with leucine at codon 238 of the EPG5 protein (p.Arg238Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs370270531, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with EPG5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.