ClinVar Genomic variation as it relates to human health
NM_001032221.6(STXBP1):c.416C>T (p.Pro139Leu)
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.416C>T (p.Pro139Leu)
Variation ID: 207415 Accession: VCV000207415.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 127661192 (GRCh38) [ NCBI UCSC ] 9: 130423471 (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 Jan 26, 2017 Feb 14, 2024 Jun 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001032221.6:c.416C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001027392.1:p.Pro139Leu missense NM_003165.6:c.416C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003156.1:p.Pro139Leu missense NM_001374306.2:c.407C>T NP_001361235.1:p.Pro136Leu missense NM_001374307.2:c.374C>T NP_001361236.1:p.Pro125Leu missense NM_001374308.2:c.374C>T NP_001361237.1:p.Pro125Leu missense NM_001374309.2:c.374C>T NP_001361238.1:p.Pro125Leu missense NM_001374310.2:c.374C>T NP_001361239.1:p.Pro125Leu missense NM_001374311.2:c.374C>T NP_001361240.1:p.Pro125Leu missense NM_001374312.2:c.374C>T NP_001361241.1:p.Pro125Leu missense NM_001374313.2:c.416C>T NP_001361242.1:p.Pro139Leu missense NM_001374314.1:c.416C>T NP_001361243.1:p.Pro139Leu missense NM_001374315.2:c.416C>T NP_001361244.1:p.Pro139Leu missense NC_000009.12:g.127661192C>T NC_000009.11:g.130423471C>T NG_016623.1:g.53986C>T NG_065187.1:g.71C>T - Protein change
- P139L, P125L, P136L
- Other names
- p.P139L:CCG>CTG
- Canonical SPDI
- NC_000009.12:127661191: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
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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 (1) |
criteria provided, single submitter
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Apr 3, 2023 | RCV000189597.15 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jun 3, 2019 | RCV000416131.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 19, 2023 | RCV001061798.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 26, 2018 | RCV000851509.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 10, 2020 | RCV001260844.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2022 | RCV002252038.9 |
Submissions - Germline
Classification
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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
(Oct 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV000680006.1
First in ClinVar: Jan 26, 2017 Last updated: Jan 26, 2017 |
Comment:
A heterozygous nonsense variant was identified, NM_003165.3(STXBP1):c.416C>T in exon 6 of the STXBP1 gene (chr9:130423471). This substitution is predicted to create a change of a … (more)
A heterozygous nonsense variant was identified, NM_003165.3(STXBP1):c.416C>T in exon 6 of the STXBP1 gene (chr9:130423471). This substitution is predicted to create a change of a proline to a leucine at amino acid position 139, NP_003156.1(STXBP1):p.(Pro139Leu). The proline at this position has high conservation and is located in a SEC1-like domain. Grantham assessment is likely pathogenic for this variant due to conservation. In silico software predicts this variant to be disease causing. This variant has not been previously observed in our patient cohort and has not been observed in population databases. It has been previously reported in patients with epileptic encephalopathies (Barcia G. et al. 2014, Eur J Med Genet; Keogh MJ. et al, 2016, Neurogenetics, ClinVar). Parental testing confirmed de novo status. Based on current information this variant has been classified as PATHOGENIC. (less)
Number of individuals with the variant: 1
Clinical Features:
Sensorineural hearing impairment (present) , Seizures (present) , Infantile encephalopathy (present) , Global developmental delay (present)
Sex: female
Tissue: Blood
Secondary finding: no
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Likely pathogenic
(Jan 01, 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:
de novo
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NeuroMeGen, Hospital Clinico Santiago de Compostela
Accession: SCV000693796.1
First in ClinVar: Jan 26, 2017 Last updated: Jan 26, 2017 |
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Likely pathogenic
(Feb 26, 2018)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability
Seizure
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: SCV000994564.1
First in ClinVar: Sep 28, 2019 Last updated: Sep 28, 2019 |
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Pathogenic
(Jun 03, 2019)
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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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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429392.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Comment:
This variant was identified as de novo (maternity and paternity confirmed).
Number of individuals with the variant: 1
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Pathogenic
(Sep 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
de novo
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Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV001437940.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
Observation 1:
Method: targeted next-gen sequencing
Observation 2:
Method: targeted next-gen sequencing
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Pathogenic
(Apr 03, 2023)
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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: SCV000243240.15
First in ClinVar: Aug 07, 2015 Last updated: Apr 09, 2023 |
Comment:
The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis … (more)
The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28133863, 35007884, 31344879, 34758253, 31780880, 27069701, 24189369, 29997391, 33176815, 28191889, 25418441, 33004838, 35851549) (less)
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Pathogenic
(Jun 19, 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: SCV001226556.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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, … (more)
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. ClinVar contains an entry for this variant (Variation ID: 207415). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 25418441, 28133863). 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 139 of the STXBP1 protein (p.Pro139Leu). (less)
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Likely pathogenic
(Jan 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523009.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PS4, PM2, PM6, PP2, PP3
Clinical Features:
Small hand (present) , Short foot (present) , Seizure (present) , Obesity (present) , Neurodevelopmental abnormality (present) , Hypotonia (present)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Developmental and epileptic encephalopathy, 4
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760226.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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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: SCV000494035.2
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 |
Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression. | Olson HE | Annals of neurology | 2017 | PMID: 28133863 |
Early epileptic encephalopathies associated with STXBP1 mutations: Could we better delineate the phenotype? | Barcia G | European journal of medical genetics | 2014 | PMID: 24189369 |
Text-mined citations for rs796053353 ...
HelpRecord last updated May 01, 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.