_x000D_ Criteria applied: PVS1, PS4, PM2_SUP, PP3
ClinVar Genomic variation as it relates to human health
NM_006772.3(SYNGAP1):c.333del (p.Lys114fs)
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
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NM_006772.3(SYNGAP1):c.333del (p.Lys114fs)
Variation ID: 430456 Accession: VCV000430456.23
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 6p21.32 6: 33432198 (GRCh38) [ NCBI UCSC ] 6: 33399975 (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 Jul 2, 2017 Mar 23, 2024 Sep 8, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006772.3:c.333del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006763.2:p.Lys114fs frameshift NM_001130066.2:c.333del NP_001123538.1:p.Lys114fs frameshift NM_006772.2:c.333del NC_000006.12:g.33432198del NC_000006.11:g.33399975del NG_016137.2:g.17129del LRG_1193:g.17129del LRG_1193t1:c.333del LRG_1193p1:p.Lys114fs - Protein change
- K114fs
- Other names
- -
- Canonical SPDI
- NC_000006.12:33432197:A:
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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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| SYNGAP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
335 | 1603 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 20, 2023 | RCV000493489.11 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 8, 2023 | RCV000689750.14 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 27, 2018 | RCV001265345.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 4, 2017 | RCV000624491.3 |
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. |
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Pathogenic
(Sep 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905639.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Clinical Features:
Autistic behavior (present) , Motor stereotypies (present) , Hypotonia (present) , Poor motor coordination (present) , Cognitive impairment (present)
Sex: male
|
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Pathogenic
(Sep 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002072200.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Pathogenic
(Jun 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 5
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002549834.1
First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022 |
Comment:
_x000D_ Criteria applied: PVS1, PS4, PM2_SUP, PP3
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Pathogenic
(Apr 04, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742364.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Delayed speech and language development (present) , Global developmental delay (present) , Intellectual disability, mild (present) , Seizures (present) , Atonic seizures (present) , Absence … (more)
Delayed speech and language development (present) , Global developmental delay (present) , Intellectual disability, mild (present) , Seizures (present) , Atonic seizures (present) , Absence seizures (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
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Pathogenic
(Jun 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000583260.5
First in ClinVar: Jul 02, 2017 Last updated: Jul 01, 2023 |
Comment:
Reported previously in the heterozygous state in a patient with epileptic encephalopathy, moderate intellectual disability, and autism spectrum disorder (Carvill et al., 2013); Frameshift variant … (more)
Reported previously in the heterozygous state in a patient with epileptic encephalopathy, moderate intellectual disability, and autism spectrum disorder (Carvill et al., 2013); Frameshift 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: 31395010, 25418537, 30541864, 23708187, 31440721) (less)
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Pathogenic
(Sep 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal dominant 5
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000817416.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430456). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430456). This premature translational stop signal has been observed in individual(s) with autism and/or intellectual disability (PMID: 25418537). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys114Serfs*20) in the SYNGAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SYNGAP1 are known to be pathogenic (PMID: 23161826, 23708187, 26989088). (less)
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Pathogenic
(Apr 27, 2018)
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no assertion criteria provided
Method: provider interpretation
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Infantile epilepsy syndrome
Affected status: yes
Allele origin:
unknown,
de novo
|
GenomeConnect - Simons Searchlight
Accession: SCV001443464.1
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 2018-04-27 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 2018-04-27 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:
Caesarian section (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Clumsiness (present) , Seizures (present) , Absence … (more)
Caesarian section (present) , Poor suck (present) , Neonatal hypotonia (present) , Feeding difficulties in infancy (present) , Clumsiness (present) , Seizures (present) , Absence seizures (present) , Atonic seizures (present) , Otitis media (present) , Pneumonia (present) , Abnormality of the respiratory system (present) , Asthma (present) , Failure to thrive (present) , Short stature (present) , Abnormality of the skin (present) , Eczema (present) , Allergy (present) , Food allergy (present) , Allergic rhinitis (present) (less)
Age: 10-19 years
Sex: female
Testing laboratory: Genetic Services Laboratory,University of Chicago
Date variant was reported to submitter: 2017-08-03
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Caesarian section (present) , Hyperbilirubinemia (present) , Hearing abnormality (present) , Conductive hearing impairment (present) , Abnormality of vision (present) , Astigmatism (present) , Generalized … (more)
Caesarian section (present) , Hyperbilirubinemia (present) , Hearing abnormality (present) , Conductive hearing impairment (present) , Abnormality of vision (present) , Astigmatism (present) , Generalized hypotonia (present) , Seizures (present) , Epileptic spasms (present) , Otitis media (present) , Absence seizures (present) (less)
Age: 10-19 years
Sex: female
Testing laboratory: Fulgent Genetics,Fulgent Genetics
Date variant was reported to submitter: 2014-09-23
Testing laboratory interpretation: Pathogenic
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Intellectual disability, autosomal dominant 5
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001519038.1
First in ClinVar: Mar 18, 2021 Last updated: Mar 18, 2021 |
Sex: female
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035359.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
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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: SCV002037527.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
|
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not provided
(-)
|
no classification provided
Method: phenotyping only
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Intellectual disability, autosomal dominant 5
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Brain Gene Registry
Accession: SCV004801640.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
Variant classified as Pathogenic and reported on 09-23-2014 by Fulgent Diagnostics . Assertions are reported exactly as they appear on the patient provided laboratory report. … (more)
Variant classified as Pathogenic and reported on 09-23-2014 by Fulgent Diagnostics . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Phenotypic abnormality (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Fulgent Genetics, Fulgent Genetics
Date variant was reported to submitter: 2014-09-23
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
Reported previously in the heterozygous state in a patient with epileptic encephalopathy, moderate intellectual disability, and autism spectrum disorder (Carvill et al., 2013); Frameshift 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: 31395010, 25418537, 30541864, 23708187, 31440721)
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430456). This premature translational stop signal has been observed in individual(s) with autism and/or intellectual disability (PMID: 25418537). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys114Serfs*20) in the SYNGAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SYNGAP1 are known to be pathogenic (PMID: 23161826, 23708187, 26989088).
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-27 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
Comment:
Variant classified as Pathogenic and reported on 09-23-2014 by Fulgent Diagnostics . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
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:
_x000D_ Criteria applied: PVS1, PS4, PM2_SUP, PP3
Comment:
Reported previously in the heterozygous state in a patient with epileptic encephalopathy, moderate intellectual disability, and autism spectrum disorder (Carvill et al., 2013); Frameshift 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: 31395010, 25418537, 30541864, 23708187, 31440721)
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430456). This premature translational stop signal has been observed in individual(s) with autism and/or intellectual disability (PMID: 25418537). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys114Serfs*20) in the SYNGAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SYNGAP1 are known to be pathogenic (PMID: 23161826, 23708187, 26989088).
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-27 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
Comment:
Variant classified as Pathogenic and reported on 09-23-2014 by Fulgent Diagnostics . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. | Mignot C | Journal of medical genetics | 2016 | PMID: 26989088 |
| Recurrent de novo mutations implicate novel genes underlying simplex autism risk. | O'Roak BJ | Nature communications | 2014 | PMID: 25418537 |
| Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. | Carvill GL | Nature genetics | 2013 | PMID: 23708187 |
| Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. | Berryer MH | Human mutation | 2013 | PMID: 23161826 |
Text-mined citations for rs1131691979 ...
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 Sep 29, 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.