9-127682509-C-T

Position:

• chr9-127682509-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_001032221.6(STXBP1):​c.1651C>T​(p.Arg551Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R551G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STXBP1 NM_001032221.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.80

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 (HGNC:):

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 chr9-127682509-C-G is described in Lovd as [Likely_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 5.8379 (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 9-127682509-C-T is Pathogenic according to our data. Variant chr9-127682509-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 207440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127682509-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.1651C>T	p.Arg551Cys	missense_variant	18/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.1651C>T	p.Arg551Cys	missense_variant	18/19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.1651C>T	p.Arg551Cys	missense_variant	18/20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.1651C>T	p.Arg551Cys	missense_variant	18/19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, 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 STXBP1-related epileptic encephalopathy. (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) 0600 - Variant is located in the annotated Sec1 family domain (NCBI, PDB). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Alternative changes at the same residue, to glycine, histidine, leucine, proline and serine, have previously been classified as pathogenic in individuals with STXBP1-related disorders (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple individuals with STXBP1-related epileptic encephalopathy, and is commonly found to be de novo (ClinVar, Decipher, PMID: 26865513). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in a worm model resulted in impaired locomotion, consistent with a loss of function (PMID: 32112430). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 17, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 20, 2023	PS3, PM1, PM2, PM5, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26514728, 29186148, 23409955, 22495311, 27069701, 26865513, 28191890, 29655203, 31130284, 28714951, 31981491, 33219223, 31175295, 31785789) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -

Developmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Mar 12, 2020

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 551 of the STXBP1 protein (p.Arg551Cys). 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: 23409955, 26865513). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207440). 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%. This variant disrupts the p.Arg551 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26865513; Invitae). 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. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PS3_strong;PS5_strong;PM1_moderate;PM2_supporting;PM5_moderate;PM6_moderate;PP2_supporting;PP3_supporting -

Infantile epilepsy syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Apr 06, 2018

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-06 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	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	.;T;.;T;.;T;D;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.2	.;.;M;.;.;.;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.8	.;.;D;.;.;.;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;.;D;.;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;D;.
Vest4		0.95, 0.95
MutPred		0.82		.;.;Loss of methylation at R551 (P = 0.0985);Loss of methylation at R551 (P = 0.0985);Loss of methylation at R551 (P = 0.0985);.;Loss of methylation at R551 (P = 0.0985);.;
MVP		0.92
MPC		2.7
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
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: rs796053373; hg19: chr9-130444788; COSMIC: COSV64813774;