rs796053361

Variant names:

• chr9-127668160-G-A
• rs796053361
• NM_003165.6:c.875G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-127668160-G-A
• chr9-127668160-G-C
• chr9-127668160-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_001032221.6(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. R292C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_001032221.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 9.91

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 chr9-127668159-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, 0.97
• 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 rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.875G>A	p.Arg292His	missense_variant	Exon 10 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.875G>A	p.Arg292His	missense_variant	Exon 10 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.875G>A	p.Arg292His	missense_variant	Exon 10 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.875G>A	p.Arg292His	missense_variant	Exon 10 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 4 Pathogenic:6 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 09, 2020

Pediatric Department, Xiangya Hospital, Central South University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 18, 2024

Servicio de Genética Del Instituto Nacional de Salud Del Niño, Ministerio de Salud

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 19, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS3, PS4, PM2, PM5, PP2, PP3 -

Aug 17, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

May 11, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Sep 19, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Feb 26, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Oct 27, 2024

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 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). 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%. 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

Nov 21, 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 2018-11-21 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	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
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	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.9	.;.;M;.;.;.;M
PrimateAI	Pathogenic	0.89	D
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	D
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

Other links and lift over

dbSNP: rs796053361; hg19: chr9-130430439;