ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1004A>C (p.Gln335Pro) (rs886041622)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000377606 SCV000330321 uncertain significance not provided 2017-02-07 criteria provided, single submitter clinical testing The Q335P variant in the PTPN11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 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 Q335P 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 that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret Q335P as a variant of uncertain significance
Invitae RCV000792044 SCV000931316 uncertain significance Rasopathy 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 335 of the PTPN11 protein (p.Gln335Pro). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTPN11-related conditions. ClinVar contains an entry for this variant (Variation ID: 280410). 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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