ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1271A>G (p.Glu424Gly) (rs730881042)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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.
Invitae RCV000795849 SCV000935327 uncertain significance Rasopathy 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 424 of the SOS1 protein (p.Glu424Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs730881042, ExAC 0.01%). This variant has been observed in an individual affected with Noonan-like syndrome with loose anagen hair (PMID: 24124081). However, in that individual a pathogenic variant in a different gene was also observed, indicating that the SOS1 variant was not likely the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 181550). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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