ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1502G>A (p.Arg501Lys) (rs397507543)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033541 SCV000057446 pathogenic not provided 2013-03-18 criteria provided, single submitter clinical testing The R501K missense mutation in the PTPN11 gene has been reported previously in association with Noonan Syndrome (Tartaglia et al., 2002). The mutation lies within a region of the gene coding for the highly conserved PTP domain of the protein-tyrosine phosphatase 11. The variant is found in NOONAN panel(s).
Invitae RCV000466382 SCV000549998 pathogenic Rasopathy 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 501 of the PTPN11 protein (p.Arg501Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in 4 individuals with Noonan syndrome (PMID: 16263833, 18470943, 18562489, 19795160, 11992261). ClinVar also contains an entry for this variant (Variation ID: 40555) with at least 7 additional observations of this variant in individuals with Noonan syndrome. 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. However, this variant is not present in the population databases and has been observed in more than ten individuals with Noonan syndrome. For these reasons, this variant has been classified Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037618 SCV000061280 pathogenic Noonan syndrome 2016-01-26 criteria provided, single submitter clinical testing The p.Arg501Lys variant in PTPN11 has been reported in >10 individuals with the clinical features of Noonan syndrome and segregated with disease in 1 affected r elative (Tartaglia 2002, Limal 2006, Noordam 2008, Jefferies 2010, LMM unpublish ed data). It has not been identified in large population studies. In summary, th is variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based upon presence in multiple affected indivi duals, segregation studies, and absence in the general population.

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