Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000681093 | SCV000808548 | uncertain significance | not provided | 2018-01-30 | criteria provided, single submitter | clinical testing | The S1066T variant has not been published as pathogenic or been reported as benign to our knowledge. The S1066T variant is not observed in large population cohorts (Lek et al., 2016). The S1066T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, although no nearby missense variants have been reported in the Human Gene Mutation Database, the SOS1 gene has a low rate of benign missense variation, and missense variants are a common mechanism of disease for this gene (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. |
| Fulgent Genetics, |
RCV002493126 | SCV002787297 | uncertain significance | Fibromatosis, gingival, 1; Noonan syndrome 4 | 2021-07-26 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003655180 | SCV004513026 | uncertain significance | RASopathy | 2023-12-16 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1066 of the SOS1 protein (p.Ser1066Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 561724). 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 SOS1 protein function with a negative predictive value of 80%. 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. |
| Service de Génétique Moléculaire, |
RCV001261113 | SCV001438520 | uncertain significance | Noonan syndrome | no assertion criteria provided | clinical testing |