ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1471C>A (p.Pro491Thr) (rs397507539)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208219 SCV000264161 pathogenic Noonan syndrome 2015-09-11 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000660240 SCV000782253 pathogenic Noonan syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000033535 SCV000057440 pathogenic not provided 2014-04-22 criteria provided, single submitter clinical testing The P491T missense mutation in the PTPN11 gene has been reported previously in association with Noonan syndrome (Ezquieta et al., 2012). This mutation has also been seen several times at GeneDx in other unrelated individuals tested for a Noonan syndrome spectrum disorder. P491T is a non-conservative missense change that occurs in the highly conserved SHP-2 domain of the PTPN11 gene, where many other pathogenic mutations have been found. Other missense mutations affecting the same codon (P491H, P491S, and P491L) have been previously reported in association with Noonan syndrome (Bertola et al., 2006, and Binder et al., 2005). The variant is found in NOONAN panel(s).
Invitae RCV000694590 SCV000823041 pathogenic Rasopathy 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 491 of the PTPN11 protein (p.Pro491Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 21526175, 22465605; http://www.hkjpaed.org/details.asp?id=581&show=1234). ClinVar contains an entry for this variant (Variation ID: 40549). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Two different missense substitutions at this codon (p.Pro491Ser and p.Pro491Leu) have been determined to be pathogenic (PMID: 22465605, 22781091). This suggests that the proline residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000208219 SCV000061276 pathogenic Noonan syndrome 2013-05-21 criteria provided, single submitter clinical testing The Pro491Thr variant has been reported in at least 6 individuals with clinical features of Noonan syndrome (Chan 2006, Carcavilla Urqui 2006, Ezquieta 2012, LM M unpublished data). In one of these individuals, the variant was inherited fro m an affected mother (Chan 2006). At our laboratory, we have identified this var iant in 3 individuals with clinical features of Noonan syndrome and the variant was also identified in at least one affected family member in each case. We have also tested several additional individuals with clinical features of Noonan spe ctrum disorders who had other amino acid changes at this position (Pro491Leu, Pr o491Ser, Pro491His). In summary, this variant meets our criteria to be classifi ed as pathogenic (http://pcpgm.partners.org/LMM).

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