rs796053368

Positions:

• chr9-127678510-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 NM_003165.6(STXBP1):​c.1439C>T​(p.Pro480Leu) 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. P480S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.57

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_003165.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127678509-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 984904.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, STXBP1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 9-127678510-C-T is Pathogenic according to our data. Variant chr9-127678510-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 207432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127678510-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP1	NM_003165.6	c.1439C>T	p.Pro480Leu	missense_variant	16/20	ENST00000373302.8
STXBP1	NM_001032221.6	c.1439C>T	p.Pro480Leu	missense_variant	16/19	ENST00000373299.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP1	ENST00000373302.8	c.1439C>T	p.Pro480Leu	missense_variant	16/20	1	NM_003165.6	P3
STXBP1	ENST00000373299.5	c.1439C>T	p.Pro480Leu	missense_variant	16/19	1	NM_001032221.6	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422486 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703400

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2017	The P480L variant in the STXBP1 gene has been reported previously as a de novo variant in individuals with early-onset epileptic encephalopathy (Milh et al., 2011; Tso et al., 2014). In addition, a missense variant at this same codon (P480S) has been reported in association with STXBP1 encephalopathy (Stamberger et al., 2016). The P480L variant is not observed in large population cohorts (Lek et al., 2016). The P480L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P480L as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2017	- -

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

Pathogenic, no assertion criteria provided	clinical testing	Pediatric Department, Xiangya Hospital, Central South University	Jan 09, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2022

The c.1439C>T (p.P480L) alteration is located in exon 16 (coding exon 16) of the STXBP1 gene. This alteration results from a C to T substitution at nucleotide position 1439, causing the proline (P) at amino acid position 480 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in multiple individuals with seizures, global developmental delay, and/or movement disorders (Milh, 2011; Tso, 2014; Zhang, 2017; Zhu, 2017; Surana, 2020; Liu, 2021). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). In vitro functional studies with p.P480L showed normal levels of STXBP1 protein, but reduced interaction with Syn-1A (Devaux, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2023

This missense change has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 21770924, 24315539, 25008876, 26514728). 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 480 of the STXBP1 protein (p.Pro480Leu). ClinVar contains an entry for this variant (Variation ID: 207432). 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. -

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	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
Polyphen		1.0	.;.;D;.;.;.;D
Vest4		0.98, 0.97
MutPred		0.90		.;.;Loss of disorder (P = 0.0347);Loss of disorder (P = 0.0347);Loss of disorder (P = 0.0347);.;Loss of disorder (P = 0.0347);
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.89
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: rs796053368; hg19: chr9-130440789;