rs886041246

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001032221.6(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_001032221.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16O:2

Conservation

PhyloP100: 8.15

Variant links:

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]

STXBP1 links:

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ACMG classification

Classification made for transcript

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 the STXBP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 79 curated benign missense variants. Gene score misZ: 4.263 (above the threshold of 3.09). Trascript score misZ: 5.8379 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
STXBP1	NM_003165.6 link	c.1217G>A	p.Arg406His	missense_variant	Exon 14 of 20	ENST00000373302.8	NP_003156.1	P61764-2
STXBP1	NM_001032221.6 link	c.1217G>A	p.Arg406His	missense_variant	Exon 14 of 19	ENST00000373299.5	NP_001027392.1	P61764-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8 link	c.1217G>A	p.Arg406His	missense_variant	Exon 14 of 20	1	NM_003165.6	ENSP00000362399.3		P61764-2
STXBP1	ENST00000373299.5 link	c.1217G>A	p.Arg406His	missense_variant	Exon 14 of 19	1	NM_001032221.6	ENSP00000362396.2		P61764-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 4

Pathogenic:8Other:2

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change and different missense changes at the same codon (p.Arg406Cys, p.Arg406Gly, p.Arg406Leu / ClinVar ID: VCV000207431, VCV000419223, VCV000812768 / PMID: 26648591, 32581362) have been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279904 /PMID: 20887364). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 11, 2019

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG evidence PS2, PM2, PP2, PP3, PP5 -

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: 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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 23, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 26, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies in humanized Caenorhabditis elegans 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 (PMID: 32112430); Missense variants in this gene are often considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26865513, 24189369, 21762454, 32238909, 28191889, 33332765, 30266908, McCormick2021[BioRxiv], 29929108, 29896790, 34120799, 35007884, 25714420, 23934111, 26648591, 29191246, 29186148, 30842224, 33004838, 35851549, 31440721, 36482122, 33057194, 35982159, 20887364, 27171548, 32112430) -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 13, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STXBP1: PS2:Very Strong, PM2, PM5, PP2, PP3 -

Inborn genetic diseases

Pathogenic:1

Jun 22, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Jun 22, 2018

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

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

LIST_S2

Pathogenic

0.99

D;.;D;D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

.;.;M;.;.;.;M

PrimateAI

Pathogenic

0.90

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over