Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000196970 | SCV000250693 | uncertain significance | not provided | 2017-08-11 | criteria provided, single submitter | clinical testing | p.Ala422Thr (GCA>ACA): c.1264 G>A in exon 4 of the SKI gene (NM_003036.3) Mutations in the SKI gene cause Shprintzen-Goldberg syndrome (SGS), a rare autosomal dominant disorder characterized by craniofacial, skeletal, neurological and cardiovascular anomalies. Cardiovascular anomalies of SGS include mitral valve prolapse and aortic root dilatation. Mutations in SKI usually occur de novo in the affected individual and are not inherited from an affected parent (Greally M, 2013; Carmignac et al., 2012, Doyle et al 2012). A variant of unknown significance has been identified in the SKI gene. The A422T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A422T variant was not observed in approximately 6,400 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 A422T 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. This substitution occurs at a position that is conserved in mammals; however, T422 is present in several vertebrate species. Consequently, 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 Shprentzen-Goldberg syndrome 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. This variant was found in TAAD |
| Ambry Genetics | RCV002315620 | SCV000739596 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2018-11-26 | criteria provided, single submitter | clinical testing | The p.A422T variant (also known as c.1264G>A), located in coding exon 4 of the SKI gene, results from a G to A substitution at nucleotide position 1264. The alanine at codon 422 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001048950 | SCV001212980 | uncertain significance | Shprintzen-Goldberg syndrome | 2023-12-07 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 422 of the SKI protein (p.Ala422Thr). 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: 213707). 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. |