Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000159160 | SCV000209105 | uncertain significance | not provided | 2017-05-15 | criteria provided, single submitter | clinical testing | The E424G variant of uncertain significance in the SOS1 gene has been previously reported in an individual diagnosed with Noonan-like syndrome with loose anagen hair (Mazzanti et al., 2013); however, this individual also harbored a de novo pathogenic variant in another gene known to cause the patient's phenotype. In addition, while this variant has been identified in other individuals referred for genetic testing for Noonan syndrome and related disorders, one of these probands was also found to harbor another variant in SOS1 that likely explains the phenotype. Nevertheless, E424G is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Furthermore, E424G 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. This substitution also occurs at a position where only amino acids with similar properties to glutamate are tolerated across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. |
Labcorp Genetics |
RCV000795849 | SCV000935327 | likely pathogenic | RASopathy | 2022-12-05 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 181550). This missense change has been observed in individuals with Noonan syndrome (Invitae). This variant is present in population databases (rs730881042, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 424 of the SOS1 protein (p.Glu424Gly). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Baylor Genetics | RCV001330104 | SCV001521707 | uncertain significance | Noonan syndrome 4 | 2023-09-27 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002372038 | SCV002686331 | uncertain significance | Cardiovascular phenotype | 2020-05-04 | criteria provided, single submitter | clinical testing | The p.E424G variant (also known as c.1271A>G), located in coding exon 10 of the SOS1 gene, results from an A to G substitution at nucleotide position 1271. The glutamic acid at codon 424 is replaced by glycine, an amino acid with similar properties. This variant has been reported to co-occur with SHOC2 p.S2G (c.4A>G) in one individual with Noonan-like syndrome with loose anagen hair (Mazzanti L et al. Am. J. Med. Genet. A, 2013 Nov;161A:2756-61). 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- |
RCV001330104 | SCV002763442 | uncertain significance | Noonan syndrome 4 | criteria provided, single submitter | clinical testing | ||
Genome- |
RCV002467632 | SCV002763443 | uncertain significance | Fibromatosis, gingival, 1 | criteria provided, single submitter | clinical testing |