Submissions for variant NM_020964.3(EPG5):c.6403G>A (p.Asp2135Asn)

gnomAD frequency: 0.00030  dbSNP: rs202038268

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792450	SCV000931751	uncertain significance	Vici syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2135 of the EPG5 protein (p.Asp2135Asn). This variant is present in population databases (rs202038268, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with EPG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 639611). 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 EPG5 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GeneDx	RCV001565604	SCV001788979	uncertain significance	not provided	2020-08-12	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In addition, in silico analysis splice predictors suggest this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Neuberg Centre For Genomic Medicine, NCGM	RCV000792450	SCV005438920	uncertain significance	Vici syndrome	2023-07-22	criteria provided, single submitter	clinical testing	The missense c.6403G>Ap.Asp2135Asn variant in EPG5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asp2135Asn variant is present with allele frquency of 0.02% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidences Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism predict no damaging effect on protein structure and function for this variant. The reference amino acid at this position on EPG5 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 2135 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS.