rs796053368
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_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
Consequence
NM_003165.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
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: 0AN: 1422486Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 703400
GnomAD4 genome ? Cov.: 32
ClinVar
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:1Other: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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at