ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.3905T>C (p.Ile1302Thr) (rs750296853)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414348 SCV000490825 uncertain significance not specified 2015-10-29 criteria provided, single submitter clinical testing The I1302T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I1302T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I1302T 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. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense variants in nearby residues have not been reported in the Human Gene Mutation Database (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Invitae RCV000465195 SCV000553266 uncertain significance Rasopathy 2016-11-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1302 of the SOS1 protein (p.Ile1302Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs750296853, ExAC 0.001%) but has not been reported in the literature in individuals with a SOS1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It is not expected to cause disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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