ClinVar Miner

Submissions for variant NM_000399.5(EGR2):c.1066G>C (p.Glu356Gln) (rs751448371)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000433767 SCV000534893 likely pathogenic not provided 2017-02-07 criteria provided, single submitter clinical testing The E356Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E356Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server. The E356Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, multiple missense variants in nearby residues have been reported in Human Gene Mutation Database in association with EGR2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000638173 SCV000759659 uncertain significance Charcot-Marie-Tooth disease, type I 2017-08-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 356 of the EGR2 protein (p.Glu356Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with EGR2-related disease. ClinVar contains an entry for this variant (Variation ID: 391755). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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