ClinVar Genomic variation as it relates to human health
NM_015559.3(SETBP1):c.2572G>A (p.Glu858Lys)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015559.3(SETBP1):c.2572G>A (p.Glu858Lys)
Variation ID: 521296 Accession: VCV000521296.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.3 18: 44951912 (GRCh38) [ NCBI UCSC ] 18: 42531877 (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 15, 2018 Feb 14, 2024 Nov 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015559.3:c.2572G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056374.2:p.Glu858Lys missense NC_000018.10:g.44951912G>A NC_000018.9:g.42531877G>A NG_027527.2:g.276740G>A LRG_1150:g.276740G>A LRG_1150t1:c.2572G>A LRG_1150p1:p.Glu858Lys - Protein change
- E858K
- Other names
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- Canonical SPDI
- NC_000018.10:44951911: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
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The frequency of the allele represented by this VCV record.
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
1449 | 1495 |
Conditions - Germline
Condition
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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
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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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no classifications from unflagged records (1) |
no classifications from unflagged records
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Apr 14, 2023 | RCV000622281.3 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 8, 2017 | RCV001265286.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 14, 2023 | RCV001591399.9 | |
Pathogenic (1) |
criteria provided, single submitter
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May 6, 2021 | RCV002470936.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 2, 2022 | RCV003128414.1 |
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
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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
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Schinzel-Giedion syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767432.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with autosomal dominant intellectual disability 29 (MIM#616078) and Schinzel-Giedion midface retraction syndrome (MIM#269150), respectively. The former is caused by premature termination variants, whereas the latter is caused by missense variants resulting in increased SETBP1 protein stability. (PMIDs: 28346496, 32460883, 25217958). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as in at least five individuals, three of whom was proven to be de novo (PMID: 25363760, 33391157, Clinvar, DECIPHER). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Transcriptome analysis performed on an individual with atypical chronic myeloid leukemia who was heterozygous for this variant, demonstrated differential expression of SETBP1 target genes. However, the individual's full genotype is unknown, therefore the observed effects cannot be conclusively attributed to this variant (PMID: 23222956 ). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Mar 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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see cases
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV003804837.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG categories: PS5,PM1,PM2,PP3
Number of individuals with the variant: 1
Clinical Features:
Microcephaly (present) , Motor stereotypies (present) , Intellectual disability, profound (present)
Age: 0-9 years
Sex: female
Tissue: blood
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Pathogenic
(Jul 29, 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: SCV001822227.4
First in ClinVar: Sep 08, 2021 Last updated: Aug 05, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25028416, 25356899, 23832012, 31332282, 23222956, 25306901, 24695057, 23443343, 24127063, 28191890, 24267886, 23020937, 21037274, 20436468, 18398855, 29796729, 26185647, 29925043, 27509124, 28346496, 25663181, 25217958, 28714951, 32005694, 33391157, 34638574, 28158286, 31785789, 27824329, 28485484, 35571021) (less)
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Pathogenic
(Nov 14, 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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Invitae
Accession: SCV002286944.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 858 of the SETBP1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 858 of the SETBP1 protein (p.Glu858Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SETBP1-related conditions (PMID: 27824329, 32005694; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 521296). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SETBP1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 08, 2017)
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no assertion criteria provided
Method: provider interpretation
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Intellectual disability, autosomal dominant 29
Affected status: yes
Allele origin:
de novo
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GenomeConnect - Simons Searchlight
Accession: SCV001443403.1
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 2017-12-08 and interpreted as Likely Pathogenic. Variant was … (more)
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-12-08 and interpreted as Likely Pathogenic. Variant was initially reported on 2017-08-07 by GTR ID of laboratory name 61756. The reporting laboratory might also submit to ClinVar. (less)
Clinical Features:
Caesarian section (present) , Hyperbilirubinemia (present) , Abnormality of vision (present) , Astigmatism (present) , Generalized hypotonia (present) , Constipation (present) , Otitis media (present)
Age: 0-9 years
Sex: female
Testing laboratory: Ambry Genetics
Date variant was reported to submitter: 2017-08-07
Testing laboratory interpretation: Likely pathogenic
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Uncertain significance
(Nov 10, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741799.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Intellectual disability, severe (present) , Muscular hypotonia (present) , Joint laxity (present) , Cerebellar ataxia (present) , Relative macrocephaly (present) … (more)
Global developmental delay (present) , Intellectual disability, severe (present) , Muscular hypotonia (present) , Joint laxity (present) , Cerebellar ataxia (present) , Relative macrocephaly (present) , Low-set ears (present) , Darwin notch of helix (present) , Absent speech (present) , Gestational diabetes (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Identification of SETBP1 Mutations by Gene Panel Sequencing in Individuals With Intellectual Disability or With "Developmental and Epileptic Encephalopathy". | Leonardi E | Frontiers in neurology | 2020 | PMID: 33391157 |
The recurrent SETBP1 c.2608G > A, p.(Gly870Ser) variant in a patient with Schinzel-Giedion syndrome: an illustrative case of the utility of whole exome sequencing in a critically ill neonate. | Leone MP | Italian journal of pediatrics | 2020 | PMID: 32460883 |
Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort. | Dong X | Journal of medical genetics | 2020 | PMID: 32005694 |
Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. | Acuna-Hidalgo R | PLoS genetics | 2017 | PMID: 28346496 |
De novo genic mutations among a Chinese autism spectrum disorder cohort. | Wang T | Nature communications | 2016 | PMID: 27824329 |
Schinzel-Giedion syndrome in two Brazilian patients: Report of a novel mutation in SETBP1 and literature review of the clinical features. | Carvalho E | American journal of medical genetics. Part A | 2015 | PMID: 25663181 |
Synaptic, transcriptional and chromatin genes disrupted in autism. | De Rubeis S | Nature | 2014 | PMID: 25363760 |
Refining analyses of copy number variation identifies specific genes associated with developmental delay. | Coe BP | Nature genetics | 2014 | PMID: 25217958 |
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. | Piazza R | Nature genetics | 2013 | PMID: 23222956 |
De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. | Hoischen A | Nature genetics | 2010 | PMID: 20436468 |
Text-mined citations for rs1178702025 ...
HelpRecord last updated Feb 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.