ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1352C>G (p.Thr451Arg) (rs730880218)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587209 SCV000330770 uncertain significance not provided 2016-09-01 criteria provided, single submitter clinical testing The T451R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T451R 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 T451R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000471377 SCV000553275 uncertain significance Rasopathy 2016-12-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 451 of the SOS1 protein (p.Thr451Arg). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is present in population databases (rs730880218, ExAC 0.009%) 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000587209 SCV000698612 uncertain significance not provided 2016-12-24 criteria provided, single submitter clinical testing Variant summary: The c.1352C>G (p.Thr451Arg) in SOS1 gene is a missense change that involves a mildly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant of interest is located within Pleckstrin homology (PH) domain functional domain that is closely associated with the DH domain and the action of the DH-PH unit gates a reciprocal interaction between Ras and SOS, although the functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a frequency 0.000008 (1/121314 chrs tested), exclusively in individuals of Latino origin (0.00008; 1/11576 chrs tested). The latter frequency exceeds the estimated maximal expected allele frequency of a pathogenic variant in SOS1 gene (0.00003). The variant is present in a control population dataset of gmomAD exclusively in individuals of Latino origin: 0.000196 (7/35710chrs), suggesting that it may be a rare ethnic-specific functional polymorphism. However, since the data set is still in beta mode, this data was not captured in pbGP. The variant has not, to our knowledge, been identified in patients with NSRD via published reports but was cited as VUS by a reputable database/diagnostic laboratory. At this time there is not sufficient evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available.

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