Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 23934111, 20887364, 26817790, 24189369, 25497044, 29186148, 30174244, 27054081, 27905812, 31572294, 32139178, 30488659)
ClinVar Genomic variation as it relates to human health
NM_001032221.6(STXBP1):c.703C>T (p.Arg235Ter)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001032221.6(STXBP1):c.703C>T (p.Arg235Ter)
Variation ID: 207422 Accession: VCV000207422.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.11 9: 127666205 (GRCh38) [ NCBI UCSC ] 9: 130428484 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 24, 2016 Feb 14, 2024 Dec 6, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001032221.6:c.703C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001027392.1:p.Arg235Ter nonsense NM_003165.6:c.703C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003156.1:p.Arg235Ter nonsense NM_001374306.2:c.694C>T NP_001361235.1:p.Arg232Ter nonsense NM_001374307.2:c.661C>T NP_001361236.1:p.Arg221Ter nonsense NM_001374308.2:c.661C>T NP_001361237.1:p.Arg221Ter nonsense NM_001374309.2:c.661C>T NP_001361238.1:p.Arg221Ter nonsense NM_001374310.2:c.661C>T NP_001361239.1:p.Arg221Ter nonsense NM_001374311.2:c.661C>T NP_001361240.1:p.Arg221Ter nonsense NM_001374312.2:c.661C>T NP_001361241.1:p.Arg221Ter nonsense NM_001374313.2:c.703C>T NP_001361242.1:p.Arg235Ter nonsense NM_001374314.1:c.703C>T NP_001361243.1:p.Arg235Ter nonsense NM_001374315.2:c.703C>T NP_001361244.1:p.Arg235Ter nonsense NM_003165.3:c.[703C>T] NC_000009.12:g.127666205C>T NC_000009.11:g.130428484C>T NG_016623.1:g.58999C>T - Protein change
- R235*, R221*, R232*
- Other names
-
p.R235*:CGA>TGA
- Canonical SPDI
- NC_000009.12:127666204:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| STXBP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1086 | 1181 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Jan 7, 2022 | RCV000189604.15 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 2, 2021 | RCV000415997.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 6, 2023 | RCV000819097.13 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 12, 2018 | RCV001265520.9 | |
|
STXBP1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV003335187.1 |
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
Help
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
Help
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
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 4
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893791.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Jan 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000243247.15
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 23934111, 20887364, 26817790, 24189369, 25497044, 29186148, 30174244, 27054081, 27905812, 31572294, 32139178, 30488659) (less)
|
|
|
Pathogenic
(Dec 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000959740.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg235*) in the STXBP1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg235*) 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 epileptic encephalopathy and/or infantile spasms (PMID: 23934111, 25497044, 29186148). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207422). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 4
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV002012187.1
First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as de novoo in similarly affected individuals (ClinVar ID: VCV000207422.7, PMID: 25497044, 20887364). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Muscle weakness (present) , Delayed speech and language development (present) , Cerebellar ataxia (present) , Delayed gross motor development (present) , Delayed fine motor development … (more)
Muscle weakness (present) , Delayed speech and language development (present) , Cerebellar ataxia (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Generalized hypotonia (present) (less)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 4
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073316.1
First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022 |
Comment:
The stop gained p.R235* in STXBP1 (NM_003165.4) has been reported previously with infantile spasms (Saitsu et al, 2010; Allen et al, 2013; Boutry-Kryza et al, … (more)
The stop gained p.R235* in STXBP1 (NM_003165.4) has been reported previously with infantile spasms (Saitsu et al, 2010; Allen et al, 2013; Boutry-Kryza et al, 2014). It has been submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in 1000 Genomes as well as gnomad. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing in STXBP1. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Neurodevelopmental delay (present) , Motor delay (present) , Obesity (present) , Cerebellar ataxia (present) , Tremor (present)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
STXBP1-related disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046050.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This nonsense variant found in exon 9 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated … (more)
This nonsense variant found in exon 9 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported as a de novo change in patients with epileptic encephalopathy (PMID: 20887364, 23934111, 29186148). Loss-of-function variation in STXBP1 is an established mechanism of disease (PMID: 26384463). The c.703C>T (p.Arg235Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.703C>T (p.Arg235Ter) variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 12, 2018)
|
no assertion criteria provided
Method: provider interpretation
|
Infantile epilepsy syndrome
Affected status: yes
Allele origin:
de novo,
unknown
|
GenomeConnect - Simons Searchlight
Accession: SCV001443664.1
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 2018-04-12 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 2018-04-12 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
Sex: male
Testing laboratory: Centogene AG - the Rare Disease Company
Date variant was reported to submitter: 2015-10-15
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-08-29
Testing laboratory interpretation: Pathogenic
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926383.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952368.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Jan 09, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Developmental and epileptic encephalopathy, 4
Affected status: yes
Allele origin:
de novo
|
Pediatric Department, Xiangya Hospital, Central South University
Accession: SCV001961023.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Developmental and epileptic encephalopathy, 4
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000494037.2
First in ClinVar: Jan 26, 2017 Last updated: Oct 01, 2022 |
|
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg235*) 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 epileptic encephalopathy and/or infantile spasms (PMID: 23934111, 25497044, 29186148). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207422). For these reasons, this variant has been classified as Pathogenic.
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as de novoo in similarly affected individuals (ClinVar ID: VCV000207422.7, PMID: 25497044, 20887364). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The stop gained p.R235* in STXBP1 (NM_003165.4) has been reported previously with infantile spasms (Saitsu et al, 2010; Allen et al, 2013; Boutry-Kryza et al, 2014). It has been submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in 1000 Genomes as well as gnomad. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing in STXBP1. For these reasons, this variant has been classified as Pathogenic.
Comment:
This nonsense variant found in exon 9 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported as a de novo change in patients with epileptic encephalopathy (PMID: 20887364, 23934111, 29186148). Loss-of-function variation in STXBP1 is an established mechanism of disease (PMID: 26384463). The c.703C>T (p.Arg235Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.703C>T (p.Arg235Ter) variant is classified as Pathogenic.
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-12 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
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. |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 23934111, 20887364, 26817790, 24189369, 25497044, 29186148, 30174244, 27054081, 27905812, 31572294, 32139178, 30488659)
Comment:
This sequence change creates a premature translational stop signal (p.Arg235*) 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 epileptic encephalopathy and/or infantile spasms (PMID: 23934111, 25497044, 29186148). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207422). For these reasons, this variant has been classified as Pathogenic.
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as de novoo in similarly affected individuals (ClinVar ID: VCV000207422.7, PMID: 25497044, 20887364). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The stop gained p.R235* in STXBP1 (NM_003165.4) has been reported previously with infantile spasms (Saitsu et al, 2010; Allen et al, 2013; Boutry-Kryza et al, 2014). It has been submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in 1000 Genomes as well as gnomad. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing in STXBP1. For these reasons, this variant has been classified as Pathogenic.
Comment:
This nonsense variant found in exon 9 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported as a de novo change in patients with epileptic encephalopathy (PMID: 20887364, 23934111, 29186148). Loss-of-function variation in STXBP1 is an established mechanism of disease (PMID: 26384463). The c.703C>T (p.Arg235Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.703C>T (p.Arg235Ter) variant is classified as Pathogenic.
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-12 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| STXBP1 Encephalopathy with Epilepsy. | Adam MP | - | 2023 | PMID: 27905812 |
| A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations. | Zhu X | PLoS genetics | 2017 | PMID: 29186148 |
| Loss-of-function mutations of STXBP1 in patients with epileptic encephalopathy. | Yamamoto T | Brain & development | 2016 | PMID: 26384463 |
| Molecular characterization of a cohort of 73 patients with infantile spasms syndrome. | Boutry-Kryza N | European journal of medical genetics | 2015 | PMID: 25497044 |
| De novo mutations in epileptic encephalopathies. | Epi4K Consortium | Nature | 2013 | PMID: 23934111 |
| STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern. | Saitsu H | Epilepsia | 2010 | PMID: 20887364 |
Text-mined citations for rs796053359 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 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.