ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1493G>T (p.Arg498Leu) (rs397507542)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212896 SCV000057445 pathogenic not provided 2018-09-04 criteria provided, single submitter clinical testing The R498L pathogenic variant in the PTPN11 gene has been reported multiple times in association with NSML and Noonan syndrome (Sarkozy et al., 2004; Du-Thanh et al., 2007; Hung et al., 2007; Limongelli et al., 2007; Limongelli et al., 2008) and has also been classified in ClinVar as a pathogenic variant by another clinical laboratory (ClinVar SCV000203964.3; Landrum et al., 2016). In addition, the R498L pathogenic variant has also been observed apparently de novo in cases referred for clinical testing of RASopathies (internal data, SCV000203964.3). It 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. R498L results in 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 highly conserved position that is located within the PTP domain, which plays a role in the catalytic activity of the PTPN11 protein. Functional studies demonstrate that R498L variant weakens the interaction between the N-SH2 and PTP domains and increases levels of phosphorylated ERK (Yu et al., 2014). Finally, a different missense variant at the same residue (R498W) and multiple missense variants in nearby residues (R501K, S502T, S502A, S502L, G503R) have been reported in HGMD in association with Noonan syndrome or NSML (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824748 SCV000203964 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2013-11-11 criteria provided, single submitter clinical testing The Arg498Leu variant in PTPN11 has been previously reported in several individu als with the clinical features of LEOPARD syndrome or Noonan syndrome (Du-Thanh 2007, Hung 2007, Limongelli 2008, Sarkozy 2004). This variant was observed to ha ve occurred de novo in another proband identified in our laboratory (LMM unpubli shed data). This variant is absent in large population studies. Another amino ac id change at this position, Arg498Trp, has also been reported in individuals wit h Noonan spectrum disorders. In summary, this variant meets our criteria to be c lassified as pathogenic (http://pcpgm.partners.org/LMM).
Institute of Molecular Biology and Genetics,Federal Almazov North-West Medical Research Centre RCV000494687 SCV000494586 pathogenic Noonan syndrome 1 2016-08-16 criteria provided, single submitter research The patient has typical signs of Noonan syndrome with mild mental delay and hypertrophic cardiomyopathy
Invitae RCV000033540 SCV000659034 pathogenic Rasopathy 2019-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 498 of the PTPN11 protein (p.Arg498Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (rs397507542, ExAC no frequency). This variant has been reported in individuals affected with LEOPARD syndrome (PMID: 15121796, 17875892, 18241070) as well as an individual affected with Noonan syndrome (PMID: 17339163). This variant has been reported by another clinical laboratory to arise de novo in an individual referred for RASopathy testing (ClinVar Variation ID: 40554). Experimental studies have shown that this missense change results in increased phosphorylation activity (PMID: 24935154). This effect is hypothesized to be the result of the observed weakened interaction between two domains within the protein (N-SH2 and PTP). In summary, this is a rare missense variant that has been observed in multiple individuals affected with PTPN11-related conditions while absent from the population databases. Furthermore, experimental studies have shown that this variant results in altered enzyme activity. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626828 SCV000747531 pathogenic Scoliosis; Abnormal facial shape; Cafe-au-lait spot; Specific learning disability; Intellectual disability, mild 2017-01-01 criteria provided, single submitter clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000212896 SCV000920534 pathogenic not provided 2018-11-12 criteria provided, single submitter clinical testing
GeneReviews RCV000055886 SCV000086892 pathologic LEOPARD syndrome 1 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.

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