ClinVar Genomic variation as it relates to human health

ACMG codes:PS4, PM1, PM2, PP3

The SETBP1 c.2608G>A variant is predicted to result in the amino acid substitution p.Gly870Ser. This variant has been well-documented to be pathogenic for Schinzel-Giedion syndrome (Hoischen et al. 2010. PubMed ID: 20436468; Acuna-Hidalgo et al. 2017. PubMed ID: 28346496. Table S1 and S4). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-42531913-G-A). This variant is interpreted as pathogenic.

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. ClinVar contains an entry for this variant (Variation ID: 1035). This missense change has been observed in individual(s) with Schinzel-Giedion syndrome (PMID: 20436468, 21371013). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 870 of the SETBP1 protein (p.Gly870Ser). For these reasons, this variant has been classified as Pathogenic.

In-silico analysis tools (REVEL, CADD, and FATHMM) predict the variant to be disease-causing and affect the SETBP1 protein function. Heterozygous variants in SETBP1 are associated with the intellectual developmental disorder, autosomal dominant 29 (MIM# 616078) and Schinzel-Giedion midface retraction syndrome (MIM# 269150). The above-mentioned variant is a recurrent variant in individuals with Schinzel-Giedion midface retraction syndrome (Hoischen et al.,2010). Also, this variant was reported in the ClinVar database as a pathogenic variant in nine independent submissions (variation id. 1035).

The SETBP1 variant c.2608G>A p.(Gly870Ser) causes an amino acid change from Gly to Ser at position 870. According to HGMD Professional 2022.1, this variant has previously been described as disease causing for Schinzel-Giedion syndrome by Hoischen et al., 2010 (PMID: 20436468), Suphapeetiporn et al., 2011 (PMID: 21371013), Ko et al., 2013 (PMID: 23400866). ClinVar lists this variant (Interpretation: Pathogenic; Variation ID: 1035). It is classified as pathogenic (class 1) according to the recommendations of CENTOGENE and ACMG.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23222956). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001035 / PMID: 20436468). Different missense changes at the same codon (p.Gly870Asp, p.Gly870Cys) have been reported to be associated with SETBP1 related disorder (ClinVar ID: VCV000001034 / PMID: 20436468, 25082129). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

The c.2608G>A (p.Gly870Ser) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. This variant has been previously reported as a de novo and heterozygous change in patients with Schinzel-Giedion syndrome (PMID: 20436468, 21371013, 23400866, 26188272, 28346496, 29333303, 32460883, 23222956). Functional studies indicate this variant may lead to higher amounts of SETBP1 protein (PMID: 23222956). The c.2608G>A (p.Gly870Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/251064). The sequence data provided for the gnomAD entry shows the c.2608G>A (p.Gly870Ser) in only 12% of NGS reads in an individual reported to be over the age of 75, therefore, the gnomAD entry likely represents an age-related somatic event (PMID: 23222956, 23832012). 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.2608G>A (p.Gly870Ser) is classified as Pathogenic.

Published functional studies demonstrate a damaging effect (significant increase in cell proliferation) (Piazza et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20436468, 26188272, 21371013, 23400866, 29333303, 32460883, 18398855, Neupauerova2019[casereport], 28209656, 28881700, 28419882, 31692115, 33822276, 29549983, 29435294, 28346496, 23222956)