Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV001837203 | SCV002097692 | uncertain significance | Shprintzen-Goldberg syndrome | 2020-06-18 | criteria provided, single submitter | clinical testing | The inherited p.Ala208Val missense variant identified in SKI has not been reported in affected individuals in the literature. The variant is absent from the gnomAD database indicating it is an extremely rare allele in the general population. The affected residue is not perfectly conserved during evolution. In silico tools provide conflicting predictions about potential pathogenicity of this variant. Based on the available evidence, the inherited p.Ala208Val missense variant identified in SKI is assessed as a variant of uncertain significance. |
| Ambry Genetics | RCV002361082 | SCV002656397 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2021-09-20 | criteria provided, single submitter | clinical testing | The p.A208V variant (also known as c.623C>T), located in coding exon 1 of the SKI gene, results from a C to T substitution at nucleotide position 623. The alanine at codon 208 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. 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 | RCV001837203 | SCV004274779 | uncertain significance | Shprintzen-Goldberg syndrome | 2024-01-01 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 208 of the SKI protein (p.Ala208Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1341723). 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. |