ClinVar Miner

Submissions for variant NM_003165.4(STXBP1):c.416C>T (p.Pro139Leu) (rs796053353)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189597 SCV000243240 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing The P139L pathogenic variant in the STXBP1 gene has been observed de novo in several individuals with early-onset epilepsy in the literature and at GeneDx (Keogh et al., 2015; Olson et al., 2017). The P139L variant is not observed in large population cohorts (Lek et al., 2016). The P139L 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. Therefore, the presence of P139L is consistent with the diagnosis of an STXBP1-related disorder in this individual.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000416131 SCV000680006 pathogenic Early infantile epileptic encephalopathy 4 2016-10-06 criteria provided, single submitter clinical testing A heterozygous nonsense variant was identified, NM_003165.3(STXBP1):c.416C>T in exon 6 of the STXBP1 gene (chr9:130423471). This substitution is predicted to create a change of a proline to a leucine at amino acid position 139, NP_003156.1(STXBP1):p.(Pro139Leu). The proline at this position has high conservation and is located in a SEC1-like domain. Grantham assessment is likely pathogenic for this variant due to conservation. In silico software predicts this variant to be disease causing. This variant has not been previously observed in our patient cohort and has not been observed in population databases. It has been previously reported in patients with epileptic encephalopathies (Barcia G. et al. 2014, Eur J Med Genet; Keogh MJ. et al, 2016, Neurogenetics, ClinVar). Parental testing confirmed de novo status. Based on current information this variant has been classified as PATHOGENIC.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000416131 SCV000693796 likely pathogenic Early infantile epileptic encephalopathy 4 2018-01-01 criteria provided, single submitter clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine RCV000851509 SCV000994564 likely pathogenic Seizures; Intellectual disability 2018-02-26 criteria provided, single submitter clinical testing
Invitae RCV001061798 SCV001226556 pathogenic Early infantile epileptic encephalopathy 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 139 of the STXBP1 protein (p.Pro139Leu). 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 observed in individual(s) with early onset epileptic encephalopathy (PMID: 25418441, 28133863). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207415). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000416131 SCV000494035 pathogenic Early infantile epileptic encephalopathy 4 2016-09-09 no assertion criteria provided literature only

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