ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1574T>C (p.Ile525Thr) (rs146722878)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000350752 SCV000329593 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing The I525T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I525T variant was not observed with any significant frequency 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 I525T 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. Additionally, this substitution occurs at a position where only amino acids with similar properties to Isoleucine are tolerated across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Phosphorus, Inc. RCV000578082 SCV000679914 uncertain significance Noonan syndrome 4 2017-08-01 criteria provided, single submitter clinical testing
Invitae RCV001051525 SCV001215682 uncertain significance Rasopathy 2019-06-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 525 of the SOS1 protein (p.Ile525Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs146722878, ExAC 0.01%). This variant has not been reported in the literature in individuals with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 279934). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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