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

gnomAD frequency: 0.00001  dbSNP: rs267607038

Total submissions: 12

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).
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.
OMIM	RCV000001086	SCV000021236	pathogenic	Schinzel-Giedion syndrome	2010-06-01	no assertion criteria provided	literature only
Gharavi Laboratory, Columbia University	RCV000255245	SCV000920674	uncertain significance	not provided	2018-09-16	flagged submission	research
PreventionGenetics, part of Exact Sciences	RCV004532268	SCV004709685	pathogenic	SETBP1-related disorder	2024-02-07	no assertion criteria provided	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.