Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000652820 | SCV000774692 | uncertain significance | Noonan syndrome 9 | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 1254 of the SOS2 protein (p.Thr1254Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 542403). 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 SOS2 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. |
| Illumina Laboratory Services, |
RCV000652820 | SCV004036000 | uncertain significance | Noonan syndrome 9 | 2023-02-10 | criteria provided, single submitter | clinical testing | The SOS2 c.3761C>G (p.Thr1254Arg) missense variant results in the substitution of threonine at amino acid position 1254 with arginine. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000015 in the European (non-Finnish) population (version 3.1.2). Almost all known pathogenic variants in the SOS2 gene reported to-date in the literature are missense variants located in a hotspot region in the N-terminus of the protein within the Dbl-homology domain between amino acids 198-388, whereas this variant is located close to the C-terminus of the protein where no pathogenic variants have been reported so far (PMID: 26173643; PMID: 32788663; PMID: 34205562). Additionally, the known pathogenic variants in this gene have either been inherited from an affected parent or occurred de novo. Based on the available evidence, the c.3761C>G (p.Thr1254Arg) variant is classified as a variant of uncertain significance for Noonan syndrome. |