Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002015914 | SCV002293530 | uncertain significance | RASopathy | 2024-06-17 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 158 of the SOS1 protein (p.Thr158Ile). This variant is present in population databases (rs776744951, gnomAD 0.006%). 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: 1500784). 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 SOS1 protein function. 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. |
| Ambry Genetics | RCV003348742 | SCV004057905 | uncertain significance | Cardiovascular phenotype | 2023-06-16 | criteria provided, single submitter | clinical testing | The p.T158I variant (also known as c.473C>T), located in coding exon 4 of the SOS1 gene, results from a C to T substitution at nucleotide position 473. The threonine at codon 158 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is conserved. 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. |
| Clinical Genomics Laboratory, |
RCV005051947 | SCV005685344 | uncertain significance | Noonan syndrome 4 | 2024-11-17 | criteria provided, single submitter | clinical testing | A SOS1 c.473C>T (p.Thr158Ile) variant was identified at a near heterozygous allelic fraction of 46.9%, a frequency which may be consistent with it being of germline origin. To our knowledge, it has not been reported in the medical literature. The SOS1 c.473C>T (p.Thr158Ile) variant has been reported in the ClinVar database (ClinVar ID: 1500784) as a germline variant of uncertain significance by two submitters. It is observed on 11/1,606,472 alleles in the general population (gnomAD v.4.1.0). Computational predictors are uncertain as to the impact of this variant on SOS1 gene function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the SOS1 c.473C>T (p.Thr158Ile) variant is uncertain at this time. |