Submissions for variant NM_020964.3(EPG5):c.5051C>T (p.Thr1684Met)

gnomAD frequency: 0.00016  dbSNP: rs188800635

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822591	SCV000963400	uncertain significance	Vici syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1684 of the EPG5 protein (p.Thr1684Met). This variant is present in population databases (rs188800635, gnomAD 0.02%). 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: 664489). 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 EPG5 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.
Ambry Genetics	RCV004029109	SCV004865687	uncertain significance	Inborn genetic diseases	2023-11-14	criteria provided, single submitter	clinical testing	The c.5051C>T (p.T1684M) alteration is located in exon 29 (coding exon 29) of the EPG5 gene. This alteration results from a C to T substitution at nucleotide position 5051, causing the threonine (T) at amino acid position 1684 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586951	SCV005075868	uncertain significance	not specified	2024-04-02	criteria provided, single submitter	clinical testing	Variant summary: EPG5 c.5051C>T (p.Thr1684Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 247930 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5051C>T in individuals affected with Vici Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 664489). Based on the evidence outlined above, the variant was classified as uncertain significance.