Submissions for variant NM_001032221.6(STXBP1):c.1217G>A (p.Arg406His)

dbSNP: rs886041246

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000369586	SCV000329541	pathogenic	not provided	2021-08-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate significantly reduced and irregular pharyngeal pumping (an indicator of neuromuscular synaptic transmission), and STXBP1 protein levels reduced to 20-30% of wild-type, suggesting the variant results in STXBP1 protein instability (Zhu et al., 2020); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 20887364, 32112430, 30266908, 33332765, McCormick2021[BioRxiv], 28191889, 32238909, 30842224, 29186148, 29896790, 29929108, 29191246, 26648591, 21762454, 23934111, 24189369, 26865513, 25714420)
Invitae	RCV000458588	SCV000547214	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 406 of the STXBP1 protein (p.Arg406His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 20887364, 21762454, 23934111, 25714420, 26514728). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 279904). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000369586	SCV000706593	pathogenic	not provided	2017-03-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622955	SCV000741589	pathogenic	Inborn genetic diseases	2016-06-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000416146	SCV000893792	pathogenic	Developmental and epileptic encephalopathy, 4	2018-10-31	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV000416146	SCV001160791	likely pathogenic	Developmental and epileptic encephalopathy, 4	2019-12-11	criteria provided, single submitter	research	ACMG evidence PS2, PM2, PP2, PP3, PP5
CeGaT Center for Human Genetics Tuebingen	RCV000369586	SCV001246976	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	STXBP1: PS2:Very Strong, PM2, PM5, PP2, PP3
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000416146	SCV001430079	pathogenic	Developmental and epileptic encephalopathy, 4	2019-07-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000416146	SCV001440145	pathogenic	Developmental and epileptic encephalopathy, 4	2019-01-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000416146	SCV002579938	pathogenic	Developmental and epileptic encephalopathy, 4	2022-05-17	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000416146	SCV004042675	pathogenic	Developmental and epileptic encephalopathy, 4		criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000416146	SCV005042809	pathogenic	Developmental and epileptic encephalopathy, 4		criteria provided, single submitter	clinical testing	The missense variant c.1217G>A p.Arg406His in STXBP1 gene has been reported in heterozygous state in multiple individuals with early-onset epileptic encephalopathy Benson KA, et al., 2020, Zhu B, et al., 2020. Experimental studies show that STXBP1 protein levels of this variant is reduced to 20-30% of wild-type, suggesting the variant results in STXBP1 protein instability Zhu B, et al., 2020. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Arginine at position 406 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Arg406His in STXBP1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV000416146	SCV000494041	not provided	Developmental and epileptic encephalopathy, 4		no assertion provided	literature only
GenomeConnect - Simons Searchlight	RCV001265512	SCV001443656	pathogenic	Infantile epilepsy syndrome	2018-06-22	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-06-22 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
GenomeConnect - Invitae Patient Insights Network	RCV000416146	SCV001749329	not provided	Developmental and epileptic encephalopathy, 4		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 04-16-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000369586	SCV002033847	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000369586	SCV002035153	pathogenic	not provided		no assertion criteria provided	clinical testing