ClinVar Miner

Submissions for variant NM_003165.4(STXBP1):c.1439C>T (p.Pro480Leu) (rs796053368)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189615 SCV000243260 pathogenic not provided 2017-11-10 criteria provided, single submitter clinical testing The P480L variant in the STXBP1 gene has been reported previously as a de novo variant in individuals with early-onset epileptic encephalopathy (Milh et al., 2011; Tso et al., 2014). In addition, a missense variant at this same codon (P480S) has been reported in association with STXBP1 encephalopathy (Stamberger et al., 2016). The P480L variant is not observed in large population cohorts (Lek et al., 2016). The P480L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P480L as a pathogenic variant.
Invitae RCV000471170 SCV000547216 pathogenic Early infantile epileptic encephalopathy 2017-01-14 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 480 of the STXBP1 protein (p.Pro480Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 4 individuals affected with early-onset epileptic encephalopathy (PMID:  21770924, 24315539, 25008876, 26514728). In three of these individuals, for whom parental testing was possible, this variant was shown to arise de novo (PMID: 21770924, 24315539, 27652284). ClinVar contains an entry for this variant (Variation ID: 207432). 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. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000189615 SCV001246979 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
GeneReviews RCV000415832 SCV000494042 pathogenic Early infantile epileptic encephalopathy 4 2016-09-09 no assertion criteria provided literature only

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