rs796053361

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The ENST00000373299.5(STXBP1):c.875G>A(p.Arg292His) 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. 12/21 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. R292P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

STXBP1
ENST00000373299.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 9.91

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 19 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000373299.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-127668159-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 5.8379 (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, 0.97

PP5

Variant 9-127668160-G-A is Pathogenic according to our data. Variant chr9-127668160-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127668160-G-A is described in Lovd as [Pathogenic]. Variant chr9-127668160-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP1	NM_003165.6 linkuse as main transcript	c.875G>A	p.Arg292His	missense_variant	10/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6 linkuse as main transcript	c.875G>A	p.Arg292His	missense_variant	10/19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8 linkuse as main transcript	c.875G>A	p.Arg292His	missense_variant	10/20	1	NM_003165.6	ENSP00000362399	P3	P61764-2
STXBP1	ENST00000373299.5 linkuse as main transcript	c.875G>A	p.Arg292His	missense_variant	10/19	1	NM_001032221.6	ENSP00000362396	A1	P61764-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 4

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 17, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Department, Xiangya Hospital, Central South University	Jan 09, 2020	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Servicio de Genética Del Instituto Nacional de Salud Del Niño, Ministerio de Salud	Nov 18, 2024	The variant NM_003165.6:c.875G>A (p.Arg292His) results in a missense mutation, substituting arginine with histidine at codon 292. This change may affect the protein’s structure and function. Based on ACMG/AMP guidelines, this variant meets the criteria for PS2, PM1, PP2, PM2, PM5, PP3, and PP5, supporting its classification as pathogenic. The evidence includes the predicted functional impact of the variant, its absence in the general population, in silico predictions indicating a damaging effect on protein function, and additional supporting data such as the observation in affected individuals -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 19, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	Published functional studies in C. elegans demonstrated that the transgenic R292H strain exhibited significantly reduced body bends on agar and showed significantly defective locomotion compared to worms expressing wild-type, and STXBP1 protein levels were reduced to 20-30% of wild-type, suggesting the variant results in STXBP1 protein instability (Zhu et al., 2020); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19804848, 26795593, 30654231, 24781210, 26865513, 28628100, 29778030, 27779742, 29314583, 29896790, 29655203, 31171384, 31780880, 27905812, 26993267, 31105003, 32112430) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2015

- -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 292 of the STXBP1 protein (p.Arg292His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental/intellectual delay and seizures (PMID: 24781210, 26865513, 27779742). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207424). 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. This variant disrupts the p.Arg292 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26865513). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Nov 21, 2018

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-11-21 and interpreted as Pathogenic. Variant was initially reported on 2018-06-15 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

.;T;.;T;.;T;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.97

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

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.9

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.7

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

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99, 0.98

MutPred

0.86

.;.;Loss of stability (P = 0.0769);Loss of stability (P = 0.0769);Loss of stability (P = 0.0769);.;Loss of stability (P = 0.0769);

MVP

0.91

MPC

1.5

ClinPred

1.0

GERP RS

4.8

Varity_R

0.85

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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