ClinVar Miner

Submissions for variant NM_003165.4(STXBP1):c.847G>A (p.Glu283Lys) (rs587777310)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000440506 SCV000517284 pathogenic not provided 2015-05-19 criteria provided, single submitter clinical testing The E283K missense change in the STXBP1 gene has been reported previously as a de novo variant inan individual with Dravet syndrome and severe intellectual disability (Carvill et al., 2014). It was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The E283Kvariant is a non-conservative amino acid substitution, which is likely to impact secondary protein structureas these residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is conserved across species, and missense variants in nearby residues (D285Y, R292H)have been reported in the Human Gene Mutation Database in association with STXBP1-related disorders(Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider E283K to be a pathogenic variant.
Invitae RCV000525775 SCV000633905 pathogenic Early infantile epileptic encephalopathy 2017-06-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 283 of the STXBP1 protein (p.Glu283Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to be de novo in an individual diagnosed with Dravet syndrome (PMID: 24623842, 26865513) and an individual affected with intractable epilepsy (Invitae database). ClinVar contains an entry for this variant (Variation ID: 127076). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000114939 SCV000148837 pathogenic Early infantile epileptic encephalopathy 4 2014-04-08 no assertion criteria provided literature only

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