Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000154291 | SCV000203950 | uncertain significance | not specified | 2014-08-14 | criteria provided, single submitter | clinical testing | The Tyr337Cys variant in SOS1 has been reported in 1 individual with clinical fe atures of Noonan syndrome (Roberts 2007), but has also been reported to be prese nt in 2 unaffected individuals from one family (Personal Communication). This va riant was absent from large population studies. Studies have shown that the Tyr3 37Cys variant may impact protein function by increasing its activity though thes e results are inconclusive and these in vitro assays may not accurately represen t biological function (Smith 2013). Due to the conflicting data about this varia nt, the clinical significance of the Tyr337Cys variant is uncertain. |
Labcorp Genetics |
RCV000149848 | SCV001395229 | uncertain significance | RASopathy | 2023-10-04 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 337 of the SOS1 protein (p.Tyr337Cys). This variant is present in population databases (rs724160007, gnomAD 0.01%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143285). ClinVar contains an entry for this variant (Variation ID: 162463). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SOS1 function (PMID: 17143285, 23487764). 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. |
Gene |
RCV001565431 | SCV001788772 | uncertain significance | not provided | 2024-09-05 | criteria provided, single submitter | clinical testing | Identified in a patient with features of Noonan syndrome in published literature (PMID: 17143285); Functional studies show conflicting results regarding the potential effect the Y337C variant has on protein function (PMID: 17143285, 23487764); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 23487764, 24803665, 29493581, 17143285) |
Ambry Genetics | RCV002319443 | SCV002608660 | uncertain significance | Cardiovascular phenotype | 2021-08-18 | criteria provided, single submitter | clinical testing | The p.Y337C variant (also known as c.1010A>G), located in coding exon 8 of the SOS1 gene, results from an A to G substitution at nucleotide position 1010. The tyrosine at codon 337 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in an individual with reported clinical diagnosis of Noonan syndrome (Roberts AE et al. Nat Genet, 2007 Jan;39:70-4). In vitro studies by one group suggested this variant had no functional impact, while studies from a second group reported some increase in pERK compared to wild type (Roberts AE et al. Nat Genet, 2007 Jan;39:70-4; Smith MJ et al. Proc Natl Acad Sci U S A, 2013 Mar;110:4574-9).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Genome- |
RCV002467591 | SCV002763469 | uncertain significance | Noonan syndrome 4 | criteria provided, single submitter | clinical testing | ||
Genome- |
RCV002467590 | SCV002763470 | uncertain significance | Fibromatosis, gingival, 1 | criteria provided, single submitter | clinical testing | ||
Fulgent Genetics, |
RCV002498685 | SCV002812726 | uncertain significance | Fibromatosis, gingival, 1; Noonan syndrome 4 | 2021-08-17 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000149848 | SCV000196693 | uncertain significance | RASopathy | no assertion criteria provided | clinical testing | Variant classified using ACMG guidelines |