ClinVar Miner

Submissions for variant NM_001032221.6(STXBP1):c.560C>T (p.Pro187Leu)

dbSNP: rs1841141204
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001863164 SCV002170989 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2023-04-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STXBP1 protein function. ClinVar contains an entry for this variant (Variation ID: 996681). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 30504930, 31175295, 33272087). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 187 of the STXBP1 protein (p.Pro187Leu).
3billion RCV002051934 SCV002318669 likely pathogenic Developmental and epileptic encephalopathy, 4 2022-03-22 criteria provided, single submitter clinical testing he variant has been previously reported as de novo in a similarly affected individual (PMID: 30504930). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.95>=0.6, 3CNET: 0.981>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics RCV002350505 SCV002654153 likely pathogenic Inborn genetic diseases 2019-06-06 criteria provided, single submitter clinical testing The p.P187L variant (also known as c.560C>T), located in coding exon 7 of the STXBP1 gene, results from a C to T substitution at nucleotide position 560. The proline at codon 187 is replaced by leucine, an amino acid with similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of STXBP1-related epileptic encephalopathy (Ambry internal data). Based on internal structural assessment, this alteration results in destabilization of the structure of STXBP1 (Ambry internal data; Colbert KN et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Jul;110:12637-42). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV002051934 SCV002764917 pathogenic Developmental and epileptic encephalopathy, 4 2021-02-02 criteria provided, single submitter clinical testing
GeneDx RCV003329397 SCV004036847 pathogenic not provided 2023-09-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31175295, 33272087, 30504930)
Institute of Human Genetics, University of Leipzig Medical Center RCV002051934 SCV004100738 pathogenic Developmental and epileptic encephalopathy, 4 2023-10-17 criteria provided, single submitter clinical testing Criteria applied: PS2_VSTR,PS4_MOD,PM2_SUP,PP2,PP3
University of Washington Center for Mendelian Genomics, University of Washington RCV001291380 SCV001479854 likely pathogenic Autism spectrum disorder no assertion criteria provided research

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