ClinVar Miner

Submissions for variant NM_003165.4(STXBP1):c.704G>A (p.Arg235Gln) (rs794727970)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000180590 SCV000233061 pathogenic not provided 2015-05-26 criteria provided, single submitter clinical testing
GeneDx RCV000180590 SCV000243248 pathogenic not provided 2018-03-05 criteria provided, single submitter clinical testing The R235Q variant in the STXBP1 gene has been reported previously as a de novo finding in both an individual with intellectual disability, global developmental delay and dysmorphic facial features (Fitzgerald et al., 2015) and in an individual with neonatal seizures and severe intellectual disability (Stamberger et al., 2016). This variant has also been observed de novo in an family undergoing whole exome sequencing at GeneDx. The R235Q variant is not observed in large population cohorts (Lek et al., 2016). The R235Q 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 highly conserved across species in the STXBP1 protein. In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R235Q as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000504117 SCV000597323 pathogenic Early infantile epileptic encephalopathy 4 2017-05-15 criteria provided, single submitter clinical testing
Invitae RCV000796167 SCV000935666 pathogenic Early infantile epileptic encephalopathy 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 235 of the STXBP1 protein (p.Arg235Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with STXBP1-related encephalopathy and/or intellectual disability (PMID: 26865513, 25533962). ClinVar contains an entry for this variant (Variation ID: 199083). 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. This variant disrupts the p.Arg235 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been observed in individuals with STXBP1-related conditions (PMID: 29761117, 26865513), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Dobyns Lab,Seattle Children's Research Institute RCV000779652 SCV000916331 likely pathogenic Early infantile epileptic encephalopathy 4; Cerebellar vermis hypoplasia 2019-02-18 no assertion criteria provided research

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