ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1508G>A (p.Gly503Glu) (rs397507546)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000033548 SCV000709442 likely pathogenic not provided 2017-06-28 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000677651 SCV000803786 pathogenic LEOPARD syndrome 1 2017-08-17 criteria provided, single submitter clinical testing
GeneDx RCV000033548 SCV000057453 pathogenic not provided 2014-08-14 criteria provided, single submitter clinical testing The G503E missense mutation has been previously published in association with Noonan syndrome (Ferrero et al., 2008). The mutation lies within a region of the gene coding for the highly conserved PTP domain of the protein-tyrosine phosphatase 11 where many pathogenic mutations cluster. Moreover, other missense changes affecting the same codon (G503R; G503A) have also been reported in patients with Noonan syndrome (Ferrero et al., 2008; Jongmans et al., 2011). The G503E mutation 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. The variant is found in NOONAN panel(s).
Invitae RCV000532971 SCV000659035 pathogenic Rasopathy 2017-01-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 503 of the PTPN11 protein (p.Gly503Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Noonan syndrome (PMID: 18678287). This variant has also been shown to arise de novo in an individual affected with congenital heart disease, neurodevelopmental disability, and pituitary dwarfism (PMID: 26785492). ClinVar contains an entry for this variant (Variation ID: 40561). A different missense substitution at this codon (p.Gly503Arg) has been determined to be pathogenic (PMID: 12960218, 24754368, 19077116, 18758896, 16358218, 19737548). This suggests that the glycine 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.

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