9-127661192-C-T

Position:

• chr9-127661192-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000373299.5(STXBP1):​c.416C>T​(p.Pro139Leu) 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. 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. P139Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STXBP1 ENST00000373299.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.70

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 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 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 chr9-127661192-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 933386.Status of the report is criteria_provided_single_submitter, 1 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, 0.987
• PP5: Variant 9-127661192-C-T is Pathogenic according to our data. Variant chr9-127661192-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127661192-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.416C>T	p.Pro139Leu	missense_variant	6/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.416C>T	p.Pro139Leu	missense_variant	6/19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.416C>T	p.Pro139Leu	missense_variant	6/20	1	NM_003165.6	ENSP00000362399	P3
STXBP1	ENST00000373299.5	c.416C>T	p.Pro139Leu	missense_variant	6/19	1	NM_001032221.6	ENSP00000362396	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 4 Pathogenic:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 03, 2019	This variant was identified as de novo (maternity and paternity confirmed). -
Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Jan 01, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 06, 2016	A heterozygous nonsense variant was identified, NM_003165.3(STXBP1):c.416C>T in exon 6 of the STXBP1 gene (chr9:130423471). This substitution is predicted to create a change of a proline to a leucine at amino acid position 139, NP_003156.1(STXBP1):p.(Pro139Leu). The proline at this position has high conservation and is located in a SEC1-like domain. Grantham assessment is likely pathogenic for this variant due to conservation. In silico software predicts this variant to be disease causing. This variant has not been previously observed in our patient cohort and has not been observed in population databases. It has been previously reported in patients with epileptic encephalopathies (Barcia G. et al. 2014, Eur J Med Genet; Keogh MJ. et al, 2016, Neurogenetics, ClinVar). Parental testing confirmed de novo status. Based on current information this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP3_Strong+PS2+PS4_Moderate+PP4+PP2 -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 19, 2023

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 207415). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 25418441, 28133863). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 139 of the STXBP1 protein (p.Pro139Leu). -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 24, 2022

ACMG classification criteria: PS4, PM2, PM6, PP2, PP3 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2023

The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28133863, 35007884, 31344879, 34758253, 31780880, 27069701, 24189369, 29997391, 33176815, 28191889, 25418441, 33004838, 35851549) -

Seizure;C3714756:Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Feb 26, 2018

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Sep 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;T;.;T;.;T;D;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-9.2	.;.;.;D;.;.;.;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;.;.;D;.;.;.;D;.
Sift4G	Pathogenic	0.0010	.;D;D;D;.;.;.;D;D
Polyphen		1.0	.;.;.;D;.;.;.;D;.
Vest4		0.89, 0.90
MutPred		0.92		.;.;.;Gain of catalytic residue at E141 (P = 0.1107);Gain of catalytic residue at E141 (P = 0.1107);Gain of catalytic residue at E141 (P = 0.1107);.;Gain of catalytic residue at E141 (P = 0.1107);.;
MVP		0.90
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.95

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: rs796053353; hg19: chr9-130423471;