rs886041246

Positions:

• chr9-127675910-G-A
• chr9-127675910-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003165.6(STXBP1):​c.1217G>A​(p.Arg406His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R406C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:2
• Conservation: PhyloP100: 8.15

Genes affected

STXBP1 (HGNC:11444): (syntaxin binding protein 1) This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127675909-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STXBP1. . Gene score misZ 4.263 (greater than the threshold 3.09). Trascript score misZ 5.8329 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant non-syndromic intellectual disability, Dravet syndrome, undetermined early-onset epileptic encephalopathy, autism spectrum disorder, developmental and epileptic encephalopathy, West syndrome, atypical Rett syndrome, developmental and epileptic encephalopathy, 4.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 9-127675910-G-A is Pathogenic according to our data. Variant chr9-127675910-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127675910-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.1217G>A	p.Arg406His	missense_variant	14/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.1217G>A	p.Arg406His	missense_variant	14/19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.1217G>A	p.Arg406His	missense_variant	14/20	1	NM_003165.6	ENSP00000362399	P3
STXBP1	ENST00000373299.5	c.1217G>A	p.Arg406His	missense_variant	14/19	1	NM_001032221.6	ENSP00000362396	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 4 Pathogenic:7 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 17, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jul 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Likely pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Dec 11, 2019	ACMG evidence PS2, PM2, PP2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	STXBP1: PS2:Very Strong, PM2, PM5, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2016

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 11, 2023

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. -

Infantile epilepsy syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Jun 22, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	.;T;.;T;.;T;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	.;.;M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.9	.;.;D;.;.;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;.;D;.;.;.;D
Sift4G	Pathogenic	0.0010	.;.;D;.;.;.;D
Polyphen		1.0	.;.;D;.;.;.;D
Vest4		0.89, 0.89
MutPred		0.91		.;.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);
MVP		0.97
MPC		2.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041246; hg19: chr9-130438189;