ClinVar Genomic variation as it relates to human health
NM_015559.3(SETBP1):c.2612T>C (p.Ile871Thr)
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.
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(9); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015559.3(SETBP1):c.2612T>C (p.Ile871Thr)
Variation ID: 1031 Accession: VCV000001031.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.3 18: 44951952 (GRCh38) [ NCBI UCSC ] 18: 42531917 (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 4, 2013 Mar 16, 2024 Feb 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015559.3:c.2612T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056374.2:p.Ile871Thr missense NC_000018.10:g.44951952T>C NC_000018.9:g.42531917T>C NG_027527.2:g.276780T>C LRG_1150:g.276780T>C LRG_1150t1:c.2612T>C LRG_1150p1:p.Ile871Thr Q9Y6X0:p.Ile871Thr - Protein change
- I871T
- Other names
- NM_015559.2(SETBP1):c.2612T>C(p.Ile871Thr)
- Canonical SPDI
- NC_000018.10:44951951:T:C
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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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SETBP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1444 | 1491 |
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
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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. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 31, 2018 | RCV000001086.12 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 21, 2023 | RCV000255245.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 28, 2019 | RCV000855501.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2018 | RCV001007919.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 7, 2024 | RCV003894780.1 |
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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Pathogenic
(Nov 27, 2013)
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criteria provided, single submitter
Method: clinical testing
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Schinzel-Giedion midface retraction syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000194894.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(May 31, 2018)
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criteria provided, single submitter
Method: curation
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Schinzel-Giedion syndrome
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000803494.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
This variant is interpreted as a Pathogenic, for Schinzel-Giedion midface retraction syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple … (more)
This variant is interpreted as a Pathogenic, for Schinzel-Giedion midface retraction syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS2 => De novo (paternity and maternity confirmed) (PMID:20436468). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation observed in multiple unrelated patients. (PMID:20436468,25028416). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:28346496). (less)
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Uncertain significance
(Sep 16, 2018)
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criteria provided, single submitter
Method: research
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not provided
Affected status: no
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000920674.1
First in ClinVar: Jun 09, 2019 Last updated: Jun 09, 2019 |
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Pathogenic
(Jun 28, 2019)
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criteria provided, single submitter
Method: research
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Arthrogryposis multiplex congenita
Fetal akinesia sequence
Affected status: yes
Allele origin:
de novo
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Cirak Lab, University Hospital Cologne
Accession: SCV000996631.1
First in ClinVar: Nov 08, 2019 Last updated: Nov 08, 2019 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Turkish
Geographic origin: Turkey
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Pathogenic
(Sep 27, 2018)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal dominant 29
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Genomic Medicine Lab, University of California San Francisco
Study: CSER
Accession: SCV001167630.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Sex: male
Secondary finding: no
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Likely pathogenic
(Jul 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019182.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 07, 2024)
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criteria provided, single submitter
Method: clinical testing
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SETBP1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004709685.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The SETBP1 c.2612T>C variant is predicted to result in the amino acid substitution p.Ile871Thr. This variant has been reported to occur de novo in more … (more)
The SETBP1 c.2612T>C variant is predicted to result in the amino acid substitution p.Ile871Thr. This variant has been reported to occur de novo in more than 14 individuals with Schinzel-Giedion syndrome (Hoischen et al. 2010. PubMed ID: 20436468; Lestner et al. 2012. PubMed ID: 22473152; Miyake et al. 2015. PubMed ID: 25028416; Takeuchi et al. 2015. PubMed ID: 26096993; Acuna-Hidalgo et al. 2017. PubMed ID: 28346496). Functional studies suggested that the p.Ile871Thr variant confers increased protein stability, supporting the gain-of-function disease mechanism in Schinzel-Giedion syndrome (Acuna-Hidalgo et al. 2017. PubMed ID: 28346496). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jul 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal dominant 29
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV001528997.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with Schinzel-Giedion midface retraction … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with Schinzel-Giedion midface retraction syndrome [PMID 20436468, 28346496] (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Schinzel-Giedion syndrome
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001554503.2
First in ClinVar: Apr 13, 2021 Last updated: Mar 19, 2022 |
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Pathogenic
(Jun 23, 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: SCV000322149.8
First in ClinVar: Oct 09, 2016 Last updated: Jul 01, 2023 |
Comment:
Published functional studies demonstrate that the I871T variant alters SETBP1 function in vitro (Acuna-Hidalgo et al., 2017; Makishima et al., 2013); In silico analysis supports … (more)
Published functional studies demonstrate that the I871T variant alters SETBP1 function in vitro (Acuna-Hidalgo et al., 2017; Makishima et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23832012, 31680123, 20436468, 28346496, 22473152, 25028416, 27535533, 34782754) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Schinzel-Giedion syndrome
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046107.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a de novo change in individuals with Schinzel-Giedion syndrome (SGS) (PMID: 28346496, 20436468, 22473152, 31680123). This variant is … (more)
This variant has been previously reported as a de novo change in individuals with Schinzel-Giedion syndrome (SGS) (PMID: 28346496, 20436468, 22473152, 31680123). This variant is located in a 12-base pair hotspot region for pathogenic variation associated with SGS (PMID: 28346496). Functional studies have shown that this variant is associated with an increase in protein levels compared to wild type SETBP1 (PMID: 28346496). The c.2612T>C (p.Ile871Thr) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/251080). However, this gene may be prone to somatic variation (PMID: 34906245, 28346496) and it is not known if the variants observed in gnomAD represent germline or somatic events. This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. 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, c.2612T>C (p.Ile871Thr) is classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2010)
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no assertion criteria provided
Method: literature only
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SCHINZEL-GIEDION MIDFACE RETRACTION SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021236.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022 |
Comment on evidence:
In 5 unrelated patients with Schinzel-Giedion syndrome (269150), Hoischen et al. (2010) identified a heterozygous 2612T-C transition in the SETBP1 gene, resulting in a substitution … (more)
In 5 unrelated patients with Schinzel-Giedion syndrome (269150), Hoischen et al. (2010) identified a heterozygous 2612T-C transition in the SETBP1 gene, resulting in a substitution at a highly conserved residue, ile871-to-thr (I871T). The mutation was not found in the 8 parents from whom DNA was available, confirming the de novo nature of the mutation, and was not detected in 188 control chromosomes. One patient died at 3 months of age and another survived to 4.5 years; 2 patients were alive at the time of the report at 2 and 3 years of age, respectively; the age at death was unknown in the fifth patient. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network. | Denommé-Pichon AS | European journal of human genetics : EJHG | 2022 | PMID: 34782754 |
The genomic and clinical landscape of fetal akinesia. | Pergande M | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31680123 |
Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. | Acuna-Hidalgo R | PLoS genetics | 2017 | PMID: 28346496 |
West syndrome in a patient with Schinzel-Giedion syndrome. | Miyake F | Journal of child neurology | 2015 | PMID: 25028416 |
De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. | Hoischen A | Nature genetics | 2010 | PMID: 20436468 |
Text-mined citations for rs267607038 ...
HelpRecord last updated Mar 17, 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.