rs587784453
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_003165.6(STXBP1):c.734A>G(p.His245Arg) 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. 12/20 in silico tools predict a damaging 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. H245N) has been classified as 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.734A>G | p.His245Arg | missense_variant | 9/20 | ENST00000373302.8 | |
STXBP1 | NM_001032221.6 | c.734A>G | p.His245Arg | missense_variant | 9/19 | ENST00000373299.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STXBP1 | ENST00000373302.8 | c.734A>G | p.His245Arg | missense_variant | 9/20 | 1 | NM_003165.6 | P3 | |
STXBP1 | ENST00000373299.5 | c.734A>G | p.His245Arg | missense_variant | 9/19 | 1 | NM_001032221.6 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 4 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 11, 2022 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 17, 2013 | DNA sequence analysis of the STXBP1 gene demonstrated a sequence change, c.734A>G, in exon 9 that results in an amino acid change, p.His245Arg. This sequence change does not appear to have been previously described in patients with STXBP1-related disorders and has also not been described as a known benign sequence change in the STXBP1 gene. The p.His245Arg change affects a highly conserved amino acid residue located in a domain of the STXBP1 protein that is known to be functional. The p.His245Arg substitution appears to be deleterious using the SIFT in-silico prediction tool, and the PolyPhen-2 software predicts a probably damaging effect of the p.His245Arg substitution on the function of the STXBP1 protein. This variant was also identified to be present in the de novo state in the patient tested in our laboratory. - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His245 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26514728). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 160070). This missense change has been observed in individual(s) with epileptic encephalopathy and intellectual disability (PMID: 25693842; Invitae). 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 histidine, which is basic and polar, with arginine, which is basic and polar, at codon 245 of the STXBP1 protein (p.His245Arg). - |
Infantile epilepsy syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Dec 18, 2018 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-12-18 and interpreted as Likely Pathogenic. Variant was initially reported on 2017-10-26 by GTR ID of laboratory name 500031. The reporting laboratory might also submit to ClinVar. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at