ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1190C>T (p.Thr397Met) (rs767503386)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000321441 SCV000329567 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing The T397M 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 T397M 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, and 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. We interpret T397M as a variant of uncertain significance, which may be related to the reported speech delay, ventricular tachycardia, and cardiac hypertrophy in this individual.Although this individual's brother and father, neither of whom are reported to have clinical symptoms of a PTPN11-related disorder, also harbor the T397M variant, marked variable expressivity has been reported for PTPN11 pathogenic variants (Allanson et al., 2011).
Invitae RCV000461011 SCV000549983 uncertain significance Rasopathy 2016-08-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 397 of the PTPN11 protein (p.Thr397Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs767503386, ExAC 0.01%) but has not been reported in the literature in individuals with a PTPN11-related disease. 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. In summary, this variant is a rare missense change that is not predicted to affect 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.
Genomic Medicine Lab, University of California San Francisco RCV001007903 SCV001167609 uncertain significance Noonan syndrome 1 2018-09-27 criteria provided, single submitter clinical testing

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