ClinVar Miner

Submissions for variant NM_015559.3(SETBP1):c.2612T>C (p.Ile871Thr)

gnomAD frequency: 0.00001  dbSNP: rs267607038
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000001086 SCV000194894 pathogenic Schinzel-Giedion syndrome 2013-11-27 criteria provided, single submitter clinical testing
GeneDx RCV000255245 SCV000322149 pathogenic not provided 2023-06-23 criteria provided, single submitter clinical testing 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)
SIB Swiss Institute of Bioinformatics RCV000001086 SCV000803494 pathogenic Schinzel-Giedion syndrome 2018-05-31 criteria provided, single submitter curation 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).
Gharavi Laboratory, Columbia University RCV000255245 SCV000920674 uncertain significance not provided 2018-09-16 criteria provided, single submitter research
Cirak Lab, University Hospital Cologne RCV000855501 SCV000996631 pathogenic Fetal akinesia deformation sequence 1; Arthrogryposis multiplex congenita 2019-06-28 criteria provided, single submitter research
Genomic Medicine Lab, University of California San Francisco RCV001007919 SCV001167630 pathogenic Intellectual disability, autosomal dominant 29 2018-09-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV001007919 SCV001528997 pathogenic Intellectual disability, autosomal dominant 29 2018-07-24 criteria provided, single submitter clinical testing 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]
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000001086 SCV001554503 pathogenic Schinzel-Giedion syndrome criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000255245 SCV002019182 likely pathogenic not provided 2023-07-21 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000001086 SCV004046107 pathogenic Schinzel-Giedion syndrome criteria provided, single submitter clinical testing 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.
PreventionGenetics, part of Exact Sciences RCV004532268 SCV004709685 pathogenic SETBP1-related disorder 2024-02-07 criteria provided, single submitter clinical testing 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.
OMIM RCV000001086 SCV000021236 pathogenic Schinzel-Giedion syndrome 2010-06-01 no assertion criteria provided literature only

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