Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Center for Genomic Medicine, |
RCV000171288 | SCV000221485 | likely pathogenic | not provided | criteria provided, single submitter | research | ||
Gene |
RCV000171288 | SCV000808544 | uncertain significance | not provided | 2018-01-16 | criteria provided, single submitter | clinical testing | The Y702C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y702C variant is observed in 1/24000 (0.0042%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The Y702C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A missense variant in the same residue (Y702H) has been reported in the Human Gene Mutation Database in association with SOS1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. |
Fulgent Genetics, |
RCV002505234 | SCV002812144 | uncertain significance | Fibromatosis, gingival, 1; Noonan syndrome 4 | 2021-07-09 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV002515236 | SCV003034949 | uncertain significance | RASopathy | 2022-09-16 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Tyr702 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17143282, 23487764, 23885229, 25862627). 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 SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 191107). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. This variant is present in population databases (rs757094189, gnomAD 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 702 of the SOS1 protein (p.Tyr702Cys). |