ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1507G>C (p.Gly503Arg) (rs397507545)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000156971 SCV000206692 pathogenic Noonan syndrome 2012-06-15 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515165 SCV000611301 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000210040 SCV000057450 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing The G503R (c.1507 G>C ) missense change in in the PTPN11 gene has been reported previously in association with Noonan syndrome (Sarkozy et al., 2003; Tartaglia et al., 2006; Kratz et al., 2005; Mathur et al., 2014), and has been observed many times at GeneDx in individuals referred for Noonan syndrome genetic testing, including apparently de novo occurrences. The variant is observed in 1/22300 (0.0045%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). G503R 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. This substitution occurs at a position that is conserved across species and lies within the PTP domain of the encoded protein, which plays an essential role in catalytic activity. In silico analysis predicts this variant is probably damaging to the protein structure/function. Another nucleotide substitution that results in the same missense change, G503R (c.1507 G>A), has also been reported in association with Noonan syndrome (Tartaglia et al., 2006). In addition, other pathogenic missense variants in nearby residues (R501K, S502T, S502A, M504V) have been reported in HGMD in association with PTPN11-related disorders (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein. As the PTPN11 gene also has a low rate of benign missense variation with missense variants being a common mechanism of disease, the G503R variant is interpreted to be pathogenic.
Invitae RCV000033545 SCV000549990 pathogenic Rasopathy 2017-08-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 503 of the PTPN11 protein (p.Gly503Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant and another nucleotide change (c.1507G>A) with the same protein effect (p.Gly503Arg) have been reported in many unrelated individuals with Noonan syndrome or Leopard syndrome (PMID: 12960218, 24754368, 19077116, 18758896, 16358218, 19737548, 12717436). ClinVar contains an entry for this variant (Variation ID: 40558). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). However, structural modeling and biochemical studies indicate that this missense variant may increase phosphatase activity of PTPN11 and facilitate the activation of Shp2 (PMID: 22681964). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824750 SCV000204060 pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome 2018-03-23 criteria provided, single submitter clinical testing The p.Gly503Arg (due to c.1507G>C or c.1507G>A) variant has previously been repo rted >10 individuals with the clinical features of Noonan syndrome, including at least 2 de novo occurrences (Tartaglia 2003, Sarkozy 2003, Zenker 2004, Kratz 2 005, Lo 2008, Ezquieta 2012, LMM data). This variant has also been reported in i ndividuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML), JMM L, and Noonan syndrome with Hodgkin?s lymphoma (Tartaglia 2003, Lo 2008). It ha s not been identified in large population studies. Three other variants involvin g this codon (p.Gly503Glu, p.Gly503Ala, p.Gly503Val) have been reported as patho genic. Computational prediction tools and conservation analysis suggest that the p.Gly503Arg variant may impact the protein. In summary, this variant meets crit eria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4; PM1; PM2; PM6; PP3.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000210040 SCV000265851 pathogenic not provided 2015-10-05 criteria provided, single submitter clinical testing

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