For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6393). This premature translational stop signal has been observed in individual(s) with SYNGAP1-related disease (PMID: 19196676, 30541864). 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 creates a premature translational stop signal (p.Arg579*) 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).
ClinVar Genomic variation as it relates to human health
NM_006772.3(SYNGAP1):c.1735C>T (p.Arg579Ter)
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006772.3(SYNGAP1):c.1735C>T (p.Arg579Ter)
Variation ID: 6393 Accession: VCV000006393.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.32 6: 33440787 (GRCh38) [ NCBI UCSC ] 6: 33408564 (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 Apr 4, 2013 Sep 16, 2024 Sep 7, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006772.3:c.1735C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006763.2:p.Arg579Ter nonsense NM_001130066.2:c.1735C>T NP_001123538.1:p.Arg579Ter nonsense NC_000006.12:g.33440787C>T NC_000006.11:g.33408564C>T NG_016137.2:g.25718C>T LRG_1193:g.25718C>T LRG_1193t1:c.1735C>T LRG_1193p1:p.Arg579Ter - Protein change
- R579*
- Other names
- -
- Canonical SPDI
- NC_000006.12:33440786: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. |
|||
| SYNGAP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
335 | 1598 | |
| SYNGAP1-AS1 | - | - | - |
GRCh38 GRCh38 |
- | 1247 |
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 (2) |
criteria provided, single submitter
|
Mar 24, 2023 | RCV000006765.11 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 7, 2024 | RCV000255371.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 27, 2017 | RCV002399311.2 |
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
(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: SCV001905551.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Clinical Features:
Prominent fingertip pads (present) , Intellectual disability (present) , Global developmental delay (present) , Delayed CNS myelination (present)
Sex: female
|
|
|
Pathogenic
(Mar 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 5
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001399101.5
First in ClinVar: Jul 16, 2020 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: 6393). 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: 6393). This premature translational stop signal has been observed in individual(s) with SYNGAP1-related disease (PMID: 19196676, 30541864). 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 creates a premature translational stop signal (p.Arg579*) 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)
|
|
|
Pathogenic
(Sep 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322241.8
First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024 |
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, 29455050, 19196676, 30541864, 29390993, 28191889, 33528079, 33057194, 35982159, 33308442) (less)
|
|
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Pathogenic
(Oct 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002713801.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R579* pathogenic mutation (also known as c.1735C>T), located in coding exon 11 of the SYNGAP1 gene, results from a C to T substitution at … (more)
The p.R579* pathogenic mutation (also known as c.1735C>T), located in coding exon 11 of the SYNGAP1 gene, results from a C to T substitution at nucleotide position 1735. This alteration was detected as a de novo occurrence in an individual with sporadic nonsyndromic intellectual disability, myoclonic and absence seizures, and abnormal EEG findings (Hamdan FF et al. N. Engl. J. Med., 2009 Feb;360:599-605). In another study, authors showed that this alteration did not have a significant impact on activity dependent phosphorylated extracellular signal-regulated kinase (pERK) levels, but did disrupt SYNGAP1 protein function, suggesting that this truncating alteration results in a loss of gene function (Berryer MH et al. Hum. Mutat., 2013 Feb;34:385-94. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807984.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
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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: SCV001926289.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(Feb 05, 2009)
|
no assertion criteria provided
Method: literature only
|
INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026957.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2022 |
Comment on evidence:
In a female patient with nonsyndromic intellectual developmental disorder (MRD5; 612621), Hamdan et al. (2009) identified a de novo heterozygous 1735C-T transition in the SYNGAP1 … (more)
In a female patient with nonsyndromic intellectual developmental disorder (MRD5; 612621), Hamdan et al. (2009) identified a de novo heterozygous 1735C-T transition in the SYNGAP1 gene, resulting in an arg579-to-ter (R579X) substitution. (less)
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963343.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
Comment:
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, 29455050, 19196676, 30541864, 29390993, 28191889, 33528079, 33057194, 35982159, 33308442)
Comment:
The p.R579* pathogenic mutation (also known as c.1735C>T), located in coding exon 11 of the SYNGAP1 gene, results from a C to T substitution at nucleotide position 1735. This alteration was detected as a de novo occurrence in an individual with sporadic nonsyndromic intellectual disability, myoclonic and absence seizures, and abnormal EEG findings (Hamdan FF et al. N. Engl. J. Med., 2009 Feb;360:599-605). In another study, authors showed that this alteration did not have a significant impact on activity dependent phosphorylated extracellular signal-regulated kinase (pERK) levels, but did disrupt SYNGAP1 protein function, suggesting that this truncating alteration results in a loss of gene function (Berryer MH et al. Hum. Mutat., 2013 Feb;34:385-94. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6393). This premature translational stop signal has been observed in individual(s) with SYNGAP1-related disease (PMID: 19196676, 30541864). 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 creates a premature translational stop signal (p.Arg579*) 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:
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, 29455050, 19196676, 30541864, 29390993, 28191889, 33528079, 33057194, 35982159, 33308442)
Comment:
The p.R579* pathogenic mutation (also known as c.1735C>T), located in coding exon 11 of the SYNGAP1 gene, results from a C to T substitution at nucleotide position 1735. This alteration was detected as a de novo occurrence in an individual with sporadic nonsyndromic intellectual disability, myoclonic and absence seizures, and abnormal EEG findings (Hamdan FF et al. N. Engl. J. Med., 2009 Feb;360:599-605). In another study, authors showed that this alteration did not have a significant impact on activity dependent phosphorylated extracellular signal-regulated kinase (pERK) levels, but did disrupt SYNGAP1 protein function, suggesting that this truncating alteration results in a loss of gene function (Berryer MH et al. Hum. Mutat., 2013 Feb;34:385-94. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy. | Vlaskamp DRM | Neurology | 2019 | PMID: 30541864 |
| Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. | Mignot C | Journal of medical genetics | 2016 | PMID: 26989088 |
| Whole-Exome Sequencing in the Clinic: Lessons from Six Consecutive Cases from the Clinician's Perspective. | Volk A | Molecular syndromology | 2015 | PMID: 25852444 |
| 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 |
| Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. | Hamdan FF | The New England journal of medicine | 2009 | PMID: 19196676 |
Text-mined citations for rs121918316 ...
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.