Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000200090 | SCV000250680 | uncertain significance | not provided | 2016-03-09 | criteria provided, single submitter | clinical testing | The P434L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The P434L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P434L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis predicts this variant likely does not alter the protein structure/function. No missense mutations in nearby residues have been reported in association with disease, suggesting this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. |
| Ambry Genetics | RCV002381673 | SCV002691179 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2020-11-02 | criteria provided, single submitter | clinical testing | The p.P434L variant (also known as c.1301C>T), located in coding exon 4 of the SKI gene, results from a C to T substitution at nucleotide position 1301. The proline at codon 434 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly 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 | RCV003517146 | SCV004293171 | uncertain significance | Shprintzen-Goldberg syndrome | 2023-06-03 | criteria provided, single submitter | clinical testing | 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SKI protein function. ClinVar contains an entry for this variant (Variation ID: 213694). This variant has not been reported in the literature in individuals affected with SKI-related conditions. This variant is present in population databases (rs768068601, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 434 of the SKI protein (p.Pro434Leu). |