rs786205598

Positions:

• chr9-127668159-C-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.874C>T​(p.Arg292Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R292H) 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:12 U:1 O:1
• Conservation: PhyloP100: 4.94

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 chr9-127668160-G-A 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, 0.969
• PP5: Variant 9-127668159-C-T is Pathogenic according to our data. 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. Variant chr9-127668159-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.874C>T	p.Arg292Cys	missense_variant	10/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.874C>T	p.Arg292Cys	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	c.874C>T	p.Arg292Cys	missense_variant	10/20	1	NM_003165.6	ENSP00000362399	P3
STXBP1	ENST00000373299.5	c.874C>T	p.Arg292Cys	missense_variant	10/19	1	NM_001032221.6	ENSP00000362396	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Department, Xiangya Hospital, Central South University	Jan 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 4 (MIM#612164). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. At least three other missense variants have been reported at this residue (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals, including de novo events and in patients with STXBP1-encephalopathy (ClinVar, PMID: 26865513, 32643187). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency 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: 29655203, 29933521, 26865513, 26993267, 26112015, 29390993, 31487502, 32139178, 31105003, 31054490, 31031587, 24077912) -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2018

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2021

This sequence change replaces arginine with cysteine at codon 292 of the STXBP1 protein (p.Arg292Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 26865513). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 191238). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). 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: 25356970, 26865513, 26993267). 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. -

Spastic ataxia Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jan 04, 2021

- -

Infantile epilepsy syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Apr 15, 2019

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-04-15 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -

West syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Dec 15, 2023

- -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 06, 2013

- -

Early onset epileptic encephalopathy Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	.;T;.;T;.;T;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.9	.;.;M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.6	.;.;D;.;.;.;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	.;.;D;.;.;.;D
Sift4G	Pathogenic	0.0	.;.;D;.;.;.;D
Polyphen		1.0, 1.0	.;.;D;.;.;.;D
Vest4		0.97
MutPred		0.84		.;.;Loss of disorder (P = 0.0675);Loss of disorder (P = 0.0675);Loss of disorder (P = 0.0675);.;Loss of disorder (P = 0.0675);
MVP		0.90
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
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: rs786205598; hg19: chr9-130430438; COSMIC: COSV64812245; COSMIC: COSV64812245;