rs796053366
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003165.6(STXBP1):c.1099C>T(p.Arg367Ter) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
STXBP1
NM_003165.6 stop_gained
NM_003165.6 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 1.62
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 9-127673250-C-T is Pathogenic according to our data. Variant chr9-127673250-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 207429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127673250-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STXBP1 | NM_003165.6 | c.1099C>T | p.Arg367Ter | stop_gained | 13/20 | ENST00000373302.8 | |
STXBP1 | NM_001032221.6 | c.1099C>T | p.Arg367Ter | stop_gained | 13/19 | ENST00000373299.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STXBP1 | ENST00000373302.8 | c.1099C>T | p.Arg367Ter | stop_gained | 13/20 | 1 | NM_003165.6 | P3 | |
STXBP1 | ENST00000373299.5 | c.1099C>T | p.Arg367Ter | stop_gained | 13/19 | 1 | NM_001032221.6 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained p.R367* in STXBP1 (NM_003165.6) has been previously identified de novo in 2 individuals with features of STXBP1 encephalopathy (Stamberger 2016, Yamashita 2016). Heterozygous loss-of-function variants in the STXBP1 gene are causative for STXBP1 encephalopathy. The variant has been reported to ClinVar as Pathogenic. The p.R367* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. The p.R367* variant is a loss of function variant in the gene STXBP1, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_003156.1:p.M1Lfs*604 and 119 others. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.1099C>T;p.(Arg367*) variant creates a premature translational stop signal in the STXBP1 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26918652) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 207429; PMID: 28135719; PMID: 27159321; PMID: 26918652) - PS4. This variant is not present in population databases (rs796053366- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 27159321; 26918652) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 01, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 25533962, 28135719, 27159321] - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 06, 2016 | The p.Arg367X variant in STXBP1 has been previously identified de novo in 2 indi viduals with features of STXBP1 encephalopathy (Stamberger 2016, Yamashita 2016) , and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 367, which is predicted to lead to a tr uncated or absent protein. Heterozygous loss-of-function variants in the STXBP1 gene are causative for STXBP1 encephalopathy. In summary, this variant meets our criteria to be classified as pathogenic for STXBP1 encephalopathy in an autosom al dominant manner based upon its predicted impact to the protein, de novo occur rences in affected individuals and absence in the general population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change creates a premature translational stop signal (p.Arg367*) in the STXBP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STXBP1 are known to be pathogenic (PMID: 20887364, 26384463). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Ohtahara syndrome or early infantile epileptic encephalopathy (PMID: 26918652, 27159321). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207429). For these reasons, this variant has been classified as Pathogenic. - |
Epileptic encephalopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neurogenetics Laboratory - MEYER, AOU Meyer | Nov 16, 2016 | - - |
Cerebellar ataxia;C0040822:Tremor;C2237142:Moderate global developmental delay Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 04, 2021 | ACMG categories: PVS1,PS2,PM2,PP3,PP5 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2017 | p.Arg367Stop (CGA>TGA):c.1099 C>T in exon 13 of the STXBP1 gene (NM_003165.2)The Arg367Stop nonsense mutation in the STXBP1 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This mutation has not been reported previously to our knowledge. The variant is found in EPILEPSY panel(s). - |
Infantile epilepsy syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Nov 10, 2017 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-11-10 and interpreted as Pathogenic. Variant was initially reported on 2013-01-14 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. - |
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Sep 10, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
0.96
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at