Submissions for variant NM_001032221.6(STXBP1):c.416C>T (p.Pro139Leu)

dbSNP: rs796053353

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189597	SCV000243240	pathogenic	not provided	2023-04-03	criteria provided, single submitter	clinical testing	The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28133863, 35007884, 31344879, 34758253, 31780880, 27069701, 24189369, 29997391, 33176815, 28191889, 25418441, 33004838, 35851549)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000416131	SCV000680006	pathogenic	Developmental and 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	Developmental and 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	Seizure; Intellectual disability	2018-02-26	criteria provided, single submitter	clinical testing
Invitae	RCV001061798	SCV001226556	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-06-19	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: 207415). This missense change 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. 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 139 of the STXBP1 protein (p.Pro139Leu).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000416131	SCV001429392	pathogenic	Developmental and epileptic encephalopathy, 4	2019-06-03	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260844	SCV001437940	pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252038	SCV002523009	likely pathogenic	See cases	2022-01-24	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM2, PM6, PP2, PP3
GeneReviews	RCV000416131	SCV000494035	not provided	Developmental and epileptic encephalopathy, 4		no assertion provided	literature only
Genomics England Pilot Project, Genomics England	RCV000416131	SCV001760226	pathogenic	Developmental and epileptic encephalopathy, 4		no assertion criteria provided	clinical testing