This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in a set of 10-year-old male twins with intellectual disability, dysmorphisms, cleft palate, hyperextensibility
ClinVar Genomic variation as it relates to human health
NM_001172509.2(SATB2):c.1375C>T (p.Arg459Ter)
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.
(12)
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
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001172509.2(SATB2):c.1375C>T (p.Arg459Ter)
Variation ID: 522269 Accession: VCV000522269.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q33.1 2: 199328709 (GRCh38) [ NCBI UCSC ] 2: 200193432 (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 20, 2018 May 1, 2024 Dec 11, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001172509.2:c.1375C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001165980.1:p.Arg459Ter nonsense NM_001172517.1:c.1375C>T NP_001165988.1:p.Arg459Ter nonsense NM_015265.4:c.1375C>T NP_056080.1:p.Arg459Ter nonsense NC_000002.12:g.199328709G>A NC_000002.11:g.200193432G>A NG_016976.2:g.147558C>T - Protein change
- R459*
- Other names
- -
- Canonical SPDI
- NC_000002.12:199328708:G: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. |
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| SATB2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
643 | 822 | |
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, multiple submitters, no conflicts
|
Jul 28, 2017 | RCV000625170.10 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 11, 2023 | RCV000680089.17 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001003958.9 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Oct 5, 2023 | RCV001564846.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 3, 2017 | RCV002317378.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 29, 2022 | RCV003389057.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jul 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Isolated cleft palate
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743993.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
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Pathogenic
(Oct 24, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Isolated cleft palate
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745950.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
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Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Chromosome 2q32-q33 deletion syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894250.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Sep 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Chromosome 2q32-q33 deletion syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Baylor Genetics
Accession: SCV000807529.2
First in ClinVar: Sep 17, 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 a set of … (more)
This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in a set of 10-year-old male twins with intellectual disability, dysmorphisms, cleft palate, hyperextensibility (less)
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Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Chromosome 2q32-q33 deletion syndrome
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841999.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was 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. It has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 25533962, 28151491). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Intellectual disability (present) , Abnormal tibia morphology (present)
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Pathogenic
(Aug 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV004101204.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
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Pathogenic
(Oct 05, 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: SCV001788074.4
First in ClinVar: Aug 21, 2021 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 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28211976, 32446642, 25533962, 28135719, 29436146, 28191890, 26596517, 25326635, 32581362, 31785789) (less)
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Pathogenic
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Chromosome 2q32-q33 deletion syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003524888.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg459*) in the SATB2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg459*) in the SATB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SATB2 are known to be pathogenic (PMID: 25885067). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Glass syndrome (PMID: 26596517, 28211976). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522269). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000850482.5
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.R459* pathogenic mutation (also known as c.1375C>T), located in coding exon 7 of the SATB2 gene, results from a C to T substitution at … (more)
The p.R459* pathogenic mutation (also known as c.1375C>T), located in coding exon 7 of the SATB2 gene, results from a C to T substitution at nucleotide position 1375. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation occurred de novo in two patients with developmental delay and cleft palate (Deciphering Developmental Disorders Study. Nature, 2015 Mar;519:223-8; Lee JS et al. Clin. Genet., 2016 Jun;89:728-32). In addition to the clinical data presented in the literature, 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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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Intellectual disability
Dystonic disorder
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001161949.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: male
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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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: SCV001953050.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Chromosome 2q32-q33 deletion syndrome
Affected status: unknown
Allele origin:
de novo
|
GeneReviews
Accession: SCV000837673.2
First in ClinVar: Oct 10, 2018 Last updated: Oct 01, 2022 |
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Comment:
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was 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. It has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 25533962, 28151491). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28211976, 32446642, 25533962, 28135719, 29436146, 28191890, 26596517, 25326635, 32581362, 31785789)
Comment:
This sequence change creates a premature translational stop signal (p.Arg459*) in the SATB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SATB2 are known to be pathogenic (PMID: 25885067). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Glass syndrome (PMID: 26596517, 28211976). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522269). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R459* pathogenic mutation (also known as c.1375C>T), located in coding exon 7 of the SATB2 gene, results from a C to T substitution at nucleotide position 1375. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation occurred de novo in two patients with developmental delay and cleft palate (Deciphering Developmental Disorders Study. Nature, 2015 Mar;519:223-8; Lee JS et al. Clin. Genet., 2016 Jun;89:728-32). In addition to the clinical data presented in the literature, 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:
This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in a set of 10-year-old male twins with intellectual disability, dysmorphisms, cleft palate, hyperextensibility
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was 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. It has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 25533962, 28151491). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28211976, 32446642, 25533962, 28135719, 29436146, 28191890, 26596517, 25326635, 32581362, 31785789)
Comment:
This sequence change creates a premature translational stop signal (p.Arg459*) in the SATB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SATB2 are known to be pathogenic (PMID: 25885067). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Glass syndrome (PMID: 26596517, 28211976). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522269). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R459* pathogenic mutation (also known as c.1375C>T), located in coding exon 7 of the SATB2 gene, results from a C to T substitution at nucleotide position 1375. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation occurred de novo in two patients with developmental delay and cleft palate (Deciphering Developmental Disorders Study. Nature, 2015 Mar;519:223-8; Lee JS et al. Clin. Genet., 2016 Jun;89:728-32). In addition to the clinical data presented in the literature, 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 |
|---|---|---|---|---|
| SATB2-Associated Syndrome. | Adam MP | - | 2024 | PMID: 29023086 |
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| A de novo SATB2 mutation in monozygotic twins with cleft palate, dental anomalies, and developmental delay. | Schwartz E | American journal of medical genetics. Part A | 2017 | PMID: 28211976 |
| Clinical and molecular consequences of disease-associated de novo mutations in SATB2. | Bengani H | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28151491 |
| SATB2-associated syndrome presenting with Rett-like phenotypes. | Lee JS | Clinical genetics | 2016 | PMID: 26596517 |
| Further supporting evidence for the SATB2-associated syndrome found through whole exome sequencing. | Zarate YA | American journal of medical genetics. Part A | 2015 | PMID: 25885067 |
| Large-scale discovery of novel genetic causes of developmental disorders. | Deciphering Developmental Disorders Study | Nature | 2015 | PMID: 25533962 |
Text-mined citations for rs1553547838 ...
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 25, 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.