ClinVar Genomic variation as it relates to human health
NM_001032221.6(STXBP1):c.1651C>T (p.Arg551Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001032221.6(STXBP1):c.1651C>T (p.Arg551Cys)
Variation ID: 207440 Accession: VCV000207440.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 127682509 (GRCh38) [ NCBI UCSC ] 9: 130444788 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 29, 2016 Apr 15, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001032221.6:c.1651C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001027392.1:p.Arg551Cys missense NM_003165.6:c.1651C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003156.1:p.Arg551Cys missense NM_001374306.2:c.1642C>T NP_001361235.1:p.Arg548Cys missense NM_001374307.2:c.1609C>T NP_001361236.1:p.Arg537Cys missense NM_001374308.2:c.1609C>T NP_001361237.1:p.Arg537Cys missense NM_001374309.2:c.1609C>T NP_001361238.1:p.Arg537Cys missense NM_001374310.2:c.1609C>T NP_001361239.1:p.Arg537Cys missense NM_001374311.2:c.1609C>T NP_001361240.1:p.Arg537Cys missense NM_001374312.2:c.1609C>T NP_001361241.1:p.Arg537Cys missense NM_001374313.2:c.1651C>T NP_001361242.1:p.Arg551Cys missense NM_001374314.1:c.1651C>T NP_001361243.1:p.Arg551Cys missense NM_001374315.2:c.1543C>T NP_001361244.1:p.Arg515Cys missense NC_000009.12:g.127682509C>T NC_000009.11:g.130444788C>T NG_016623.1:g.75303C>T - Protein change
- R551C, R515C, R537C, R548C
- Other names
- p.R551C:CGC>TGC
- Canonical SPDI
- NC_000009.12:127682508:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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STXBP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1055 | 1146 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2021 | RCV000189623.26 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000415936.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 10, 2023 | RCV001071757.13 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 6, 2018 | RCV001265516.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 26, 2021 | RCV001420235.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 12, 2020 | RCV003126574.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV000615518.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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Pathogenic
(Jul 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 4
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428885.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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See cases
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli
Accession: SCV001622655.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
PS3_strong;PS5_strong;PM1_moderate;PM2_supporting;PM5_moderate;PM6_moderate;PP2_supporting;PP3_supporting
Clinical Features:
Seizure (present) , Hypotonia (present) , Gastroesophageal reflux (present)
Sex: male
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Pathogenic
(Mar 12, 2020)
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criteria provided, single submitter
Method: clinical testing
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Developmental disorder
Affected status: yes
Allele origin:
de novo
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Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV003803759.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Sex: female
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Pathogenic
(Oct 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000243268.12
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26514728, 29186148, 23409955, 22495311, 27069701, 26865513, 28191890, 29655203, 31130284, 28714951, 31981491, 33219223, 31175295, 31785789) (less)
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Pathogenic
(Nov 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 4
Affected status: yes
Allele origin:
de novo
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921960.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
0102 - Loss of function is a known mechanism of disease in this gene and is associated with STXBP1-related epileptic encephalopathy. (I) 0107 - This … (more)
0102 - Loss of function is a known mechanism of disease in this gene and is associated with STXBP1-related epileptic encephalopathy. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple <i>in silico</i> tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Sec1 family domain (NCBI, PDB). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Alternative changes at the same residue, to glycine, histidine, leucine, proline and serine, have previously been classified as pathogenic in individuals with STXBP1-related disorders (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple individuals with STXBP1-related epileptic encephalopathy, and is commonly found to be <i>de novo</i> (ClinVar, Decipher, PMID: 26865513). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in a worm model resulted in impaired locomotion, consistent with a loss of function (PMID: 32112430). (SP) 1203 - This variant has been shown to be <i>de novo</i> in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Feb 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 4
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004014018.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PS3, PM1, PM2, PM5, PP3, PP5
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Pathogenic
(Nov 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001237078.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 551 of the STXBP1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 551 of the STXBP1 protein (p.Arg551Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 23409955, 26865513). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207440). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg551 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26865513; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 4
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004808235.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jan 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246984.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 8
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Pathogenic
(Apr 06, 2018)
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no assertion criteria provided
Method: provider interpretation
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Infantile epilepsy syndrome
Affected status: yes
Allele origin:
de novo,
unknown
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GenomeConnect - Simons Searchlight
Accession: SCV001443660.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-06 and interpreted as Pathogenic. The reporting laboratory … (more)
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-06 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Seizures (present) , Absence seizures (present) , Gastroesophageal reflux (present) , Diarrhea (present) , Constipation (present) , Otitis media (present) , … (more)
Autistic behavior (present) , Seizures (present) , Absence seizures (present) , Gastroesophageal reflux (present) , Diarrhea (present) , Constipation (present) , Otitis media (present) , Abnormality of the skin (present) , Eczema (present) , Allergy (present) , Lactose intolerance (present) , Food allergy (present) , Allergic rhinitis (present) (less)
Age: 0-9 years
Sex: male
Testing laboratory: Institut de Pathologie et de Genetique Univeriteit Ziekenhuis Antwerpen
Date variant was reported to submitter: 2015-04-24
Testing laboratory interpretation: Likely pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Ventouse delivery (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding … (more)
Autistic behavior (present) , Ventouse delivery (present) , Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Generalized hypotonia (present) , Tics (present) , Cerebral palsy (present) , Seizure precipitated by febrile infection (present) , Seizures (present) , Generalized tonic-clonic seizures (present) , Focal seizures with impairment of consciousness or awareness (present) , Abnormality of digestive system morphology (present) , Gastroesophageal reflux (present) , Diarrhea (present) , Pneumonia (present) , Sinus tachycardia (present) , Failure to thrive (present) , Abnormality of the skeletal system (present) , Osteopenia (present) , Allergy (present) , Latex allergy (present) , Lactose intolerance (present) , Abnormality of the cardiovascular system (present) (less)
Sex: female
Testing laboratory: GeneDx
Testing laboratory interpretation: Pathogenic
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not provided
(-)
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no classification provided
Method: literature only
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Developmental and epileptic encephalopathy, 4
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000494043.2
First in ClinVar: Jan 26, 2017 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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STXBP1 Encephalopathy with Epilepsy. | Adam MP | - | 2023 | PMID: 27905812 |
Early Infantile Epileptic Encephalopathy in an STXBP1 Patient with Lactic Acidemia and Normal Mitochondrial Respiratory Chain Function. | Li D | Case reports in genetics | 2016 | PMID: 27069701 |
STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. | Stamberger H | Neurology | 2016 | PMID: 26865513 |
Epileptic patients with de novo STXBP1 mutations: Key clinical features based on 24 cases. | Di Meglio C | Epilepsia | 2015 | PMID: 26514728 |
Reduction of seizure frequency after epilepsy surgery in a patient with STXBP1 encephalopathy and clinical description of six novel mutation carriers. | Weckhuysen S | Epilepsia | 2013 | PMID: 23409955 |
Patterns and rates of exonic de novo mutations in autism spectrum disorders. | Neale BM | Nature | 2012 | PMID: 22495311 |
Text-mined citations for rs796053373 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.