Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000521311 | SCV000618510 | uncertain significance | not provided | 2018-03-13 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the SKI gene. The S432G variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S432G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position where amino acids with similar properties to serine (S) are tolerated across species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. |
| Ambry Genetics | RCV002384006 | SCV002692858 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-08-03 | criteria provided, single submitter | clinical testing | The p.S432G variant (also known as c.1294A>G), located in coding exon 4 of the SKI gene, results from an A to G substitution at nucleotide position 1294. The serine at codon 432 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV003631129 | SCV004518231 | uncertain significance | Shprintzen-Goldberg syndrome | 2024-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 432 of the SKI protein (p.Ser432Gly). This variant is present in population databases (rs368739670, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SKI-related conditions. ClinVar contains an entry for this variant (Variation ID: 449989). 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 not expected to disrupt SKI protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |