Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002264876 | SCV004640525 | likely pathogenic | Shprintzen-Goldberg syndrome | 2022-11-22 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly117 amino acid residue in SKI. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 SKI protein function. ClinVar contains an entry for this variant (Variation ID: 1695374). This variant has not been reported in the literature in individuals affected with SKI-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 117 of the SKI protein (p.Gly117Asp). |
| Insititute of Human Genetics, |
RCV002264876 | SCV002540748 | likely pathogenic | Shprintzen-Goldberg syndrome | 2022-07-07 | no assertion criteria provided | clinical testing | The variant NM_003036.4: c.350G>A, p.(Gly117Asp) in the SKI gene leads to the replacement of an amino acid (missense). The variant is not listed in the database gnomAD. Five of five bioinformatic evaluations predict an impact on protein function ("damaging"). The exchange of the amino acid Gly117 has already been described as a "pathogenic" variant, but in this case the glycine is exchanged with an arginine (Doyle AJ, Det al., Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet. 2012 Nov;44(11):1249-54.). The amino acid aspartate belongs to the same group as arginine (hydrophilic side chain). It is expected that the exchange of glycine to aspartate also leads to the phenotype of a Shprintzen-Goldberg syndrome, as seen in our patient. |