A mosaic c.1630C>T (p.R544X) pathogenic variant in the SYNGAP1 gene was detected in this individual (33 mutant and 256 reference reads) and was confirmed by Sanger sequencing. This variant has been previously reported as de novo in a patient with intellectual disability and developmental delay (PMID: 26989088) and is predicted to result in a premature stop codon.
ClinVar Genomic variation as it relates to human health
NM_006772.3(SYNGAP1):c.1630C>T (p.Arg544Ter)
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.
(7)
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
7
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.1630C>T (p.Arg544Ter)
Variation ID: 522845 Accession: VCV000522845.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.32 6: 33438873 (GRCh38) [ NCBI UCSC ] 6: 33406650 (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 Apr 29, 2018 Oct 20, 2024 Oct 31, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006772.3:c.1630C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006763.2:p.Arg544Ter nonsense NM_001130066.2:c.1630C>T NP_001123538.1:p.Arg544Ter nonsense NC_000006.12:g.33438873C>T NC_000006.11:g.33406650C>T NG_016137.2:g.23804C>T LRG_1193:g.23804C>T LRG_1193t1:c.1630C>T LRG_1193p1:p.Arg544Ter - Protein change
- R544*
- Other names
- -
- Canonical SPDI
- NC_000006.12:33438872: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
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 | 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 (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2022 | RCV000626018.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 26, 2021 | RCV002529771.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 31, 2023 | RCV001092254.23 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jun 16, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 5
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000746627.1 First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018 |
Comment:
A mosaic c.1630C>T (p.R544X) pathogenic variant in the SYNGAP1 gene was detected in this individual (33 mutant and 256 reference reads) and was confirmed by … (more)
A mosaic c.1630C>T (p.R544X) pathogenic variant in the SYNGAP1 gene was detected in this individual (33 mutant and 256 reference reads) and was confirmed by Sanger sequencing. This variant has been previously reported as de novo in a patient with intellectual disability and developmental delay (PMID: 26989088) and is predicted to result in a premature stop codon. (less)
Number of individuals with the variant: 1
Clinical Features:
Vertebral fusion (present) , Tall stature (present) , Short philtrum (present) , Short 5th metacarpal (present) , Severe Myopia (present) , Posteriorly rotated ears (present) … (more)
Vertebral fusion (present) , Tall stature (present) , Short philtrum (present) , Short 5th metacarpal (present) , Severe Myopia (present) , Posteriorly rotated ears (present) , Orthostatic tachycardia (present) , Narrow nasal bridge (present) , Muscular hypotonia (present) , Melanocytic nevus (present) , Macrotia (present) , Macrocephaly (present) , Lower thoracic kyphosis (present) , Intellectual disability, borderline (present) , Hyperlordosis (present) , Hyperextensibility of the finger joints (present) , Hyperextensibility at elbow (present) , High, narrow palate (present) , Genu valgum (present) , Finger joint hypermobility (present) , Downslanted palpebral fissures (present) , Delayed speech and language development (present) , Deeply set eye (present) , Clinodactyly of the 5th finger (present) , Childhood-onset truncal obesity (present) , Anisocoria (present) , Abnormality of the palate (present) , 2-3 toe syndactyly (present) (less)
Age: 30-39 years
Sex: female
Ethnicity/Population group: White
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2017-06-16
Testing laboratory interpretation: Pathogenic
|
|
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Pathogenic
(Sep 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 5
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Baylor Genetics
Accession: SCV000807555.2
First in ClinVar: Apr 29, 2018 Last updated: Dec 11, 2022 |
Comment:
This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in an 11-year-old female … (more)
This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in an 11-year-old female with Leigh disease, intellectual disability, short stature, microcephaly, failure to thrive, PDA, brachydactyly, pes planus, congenital hypothyroidism. Patient also carried compound heterozygous pathogenic variants in MTFMT. (less)
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Pathogenic
(Oct 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004170562.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 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 … (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: 31349857, 25326635, 26989088) (less)
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Pathogenic
(Aug 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003568417.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1630C>T (p.R544*) alteration, located in exon 10 (coding exon 10) of the SYNGAP1 gene, consists of a C to T substitution at nucleotide position … (more)
The c.1630C>T (p.R544*) alteration, located in exon 10 (coding exon 10) of the SYNGAP1 gene, consists of a C to T substitution at nucleotide position 1630. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 544. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported to occur de novo in a patient with severe intellectual disability, truncal hypotonia, swallowing difficulties, epilepsy, and very poor social interactions (Mignot, 2016). In addition, this alteration has also been identified in a patient with generalized epilepsy (Hoelz, 2020) and in a mosaic patient with a neurodevelopmental phenotype (Cao, 2019). Based on the available evidence, this alteration is classified as pathogenic. (less)
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|
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Pathogenic
(Dec 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
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MENTAL RETARDATION, AUTOSOMAL DOMINANT 5
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996221.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This nonsense variant found in exon 10 of 19 is predicted to result in loss of normal protein function. This variant has been previously reported … (more)
This nonsense variant found in exon 10 of 19 is predicted to result in loss of normal protein function. This variant has been previously reported as a de novo change in a patient with global developmental delay and epilepsy (PMID: 26989088). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.1630C>T (p.Arg544Ter) variant is classified as pathogenic. (less)
Number of individuals with the variant: 1
|
|
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Pathogenic
(Jul 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 5
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001209200.3
First in ClinVar: Apr 15, 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: 522845). 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: 522845). This premature translational stop signal has been observed in individual(s) with infantile epileptic encephalopathy (PMID: 26989088). 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.Arg544*) 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
(Jan 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248673.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
Comment:
Comment:
This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in an 11-year-old female with Leigh disease, intellectual disability, short stature, microcephaly, failure to thrive, PDA, brachydactyly, pes planus, congenital hypothyroidism. Patient also carried compound heterozygous pathogenic variants in MTFMT.
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: 31349857, 25326635, 26989088)
Comment:
The c.1630C>T (p.R544*) alteration, located in exon 10 (coding exon 10) of the SYNGAP1 gene, consists of a C to T substitution at nucleotide position 1630. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 544. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported to occur de novo in a patient with severe intellectual disability, truncal hypotonia, swallowing difficulties, epilepsy, and very poor social interactions (Mignot, 2016). In addition, this alteration has also been identified in a patient with generalized epilepsy (Hoelz, 2020) and in a mosaic patient with a neurodevelopmental phenotype (Cao, 2019). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
This nonsense variant found in exon 10 of 19 is predicted to result in loss of normal protein function. This variant has been previously reported as a de novo change in a patient with global developmental delay and epilepsy (PMID: 26989088). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.1630C>T (p.Arg544Ter) variant is classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 522845). This premature translational stop signal has been observed in individual(s) with infantile epileptic encephalopathy (PMID: 26989088). 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.Arg544*) 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).
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:
A mosaic c.1630C>T (p.R544X) pathogenic variant in the SYNGAP1 gene was detected in this individual (33 mutant and 256 reference reads) and was confirmed by Sanger sequencing. This variant has been previously reported as de novo in a patient with intellectual disability and developmental delay (PMID: 26989088) and is predicted to result in a premature stop codon.
Comment:
This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in an 11-year-old female with Leigh disease, intellectual disability, short stature, microcephaly, failure to thrive, PDA, brachydactyly, pes planus, congenital hypothyroidism. Patient also carried compound heterozygous pathogenic variants in MTFMT.
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: 31349857, 25326635, 26989088)
Comment:
The c.1630C>T (p.R544*) alteration, located in exon 10 (coding exon 10) of the SYNGAP1 gene, consists of a C to T substitution at nucleotide position 1630. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 544. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported to occur de novo in a patient with severe intellectual disability, truncal hypotonia, swallowing difficulties, epilepsy, and very poor social interactions (Mignot, 2016). In addition, this alteration has also been identified in a patient with generalized epilepsy (Hoelz, 2020) and in a mosaic patient with a neurodevelopmental phenotype (Cao, 2019). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
This nonsense variant found in exon 10 of 19 is predicted to result in loss of normal protein function. This variant has been previously reported as a de novo change in a patient with global developmental delay and epilepsy (PMID: 26989088). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.1630C>T (p.Arg544Ter) variant is classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 522845). This premature translational stop signal has been observed in individual(s) with infantile epileptic encephalopathy (PMID: 26989088). 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.Arg544*) 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).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Impact on Clinical Decision Making of Next-Generation Sequencing in Pediatric Epilepsy in a Tertiary Epilepsy Referral Center. | Hoelz H | Clinical EEG and neuroscience | 2020 | PMID: 31554424 |
| A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing. | Cao Y | Genome medicine | 2019 | PMID: 31349857 |
| Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. | Mignot C | Journal of medical genetics | 2016 | PMID: 26989088 |
| 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 rs1554121443 ...
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 Oct 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.