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

dbSNP: rs1841141204

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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