ClinVar Miner

Submissions for variant NM_003165.4(STXBP1):c.569G>A (p.Arg190Gln) (rs796053356)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189600 SCV000243243 pathogenic not provided 2016-09-09 criteria provided, single submitter clinical testing The R190Q variant in the STXBP1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different missense variant at the same residue (R190W) has been reported as a de novo variant in two unrelated individuals with epileptic encephalopathy (Carvill et al., 2013; Allen et al., 2013). The R190Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R190Q 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 R190Q is consistent with the diagnosis of a STXBP1-related disorder in this individual.
Invitae RCV000796165 SCV000935664 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-04-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 190 of the STXBP1 protein (p.Arg190Gln). 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 in individual(s) with seizures (PMID: 26633542, Invitae). In at least one individual the variant was inherited from an unaffected parent who was apparently germline mosaic (Invitae). ClinVar contains an entry for this variant (Variation ID: 207418). 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.Arg190 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 23708187, 23934111, 26544041, 26514728), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003592 SCV001161986 likely pathogenic Autistic disorder of childhood onset; Neurodegeneration; Photosensitive tonic-clonic seizures; Intellectual disability, severe no assertion criteria provided research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000189600 SCV001799863 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000189600 SCV001809746 pathogenic not provided no assertion criteria provided clinical testing

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