Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV001839294 | SCV002099279 | uncertain significance | Noonan syndrome 4 | 2021-03-26 | criteria provided, single submitter | clinical testing | The c.743G>T (p.Arg248Leu) variant identified in the SOS1 gene substitutes a conserved Arginine for Leucine at amino acid248/1334 (exon 6/23). This variant is found with low frequency in gnomAD(v3.1.1) (1 heterozygote, 0 homozygotes; allele frequency:6.58e-6) suggesting it is not a common benign variant in the populations in that database. In silico algorithms predict this variant to be Damaging (SIFT; score: 0.005) and Pathogenic (REVEL; score:0.633) to the function of the canonical transcript. This variant is absent from ClinVar, although a different amino acid change at the same position has been reported there as a Variant of Uncertain Significance (p.Arg248Cys; VarID:952557). To our current knowledge, the p.Arg248Leu variant identified here has not been reported in affected individuals in the literature. The p.Arg248 residue is within the Dbl Homology (DH) domain of SOS1 (UniProtKB:Q07889) which is involved in blocking allosteric Ras binding. Given the lack of compelling evidence for its pathogenicity, the c.743G>T (p.Arg248Leu) variant identified in the SOS1 gene is reported as a Variant of Uncertain Significance. |
| Labcorp Genetics |
RCV005095310 | SCV005847250 | uncertain significance | RASopathy | 2024-06-04 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 248 of the SOS1 protein (p.Arg248Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 1342543). 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. |