ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1504T>G (p.Ser502Ala) (rs121918458)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212898 SCV000884429 pathogenic not provided 2017-05-05 criteria provided, single submitter clinical testing
GeneDx RCV000212898 SCV000057447 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing The S502A variant in the PTPN11 gene has been reported previously as a de novo germline variant in patients with Noonan syndrome/ Myeloproliferative disease/ Cardiofaciocutaneous syndrome (NS/MPD/CFC) (Kratz et al., 2005; Joyce et al., 2015). The S502A substitution 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. It 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 in silico analysis predicts this variant is probably damaging to the protein structure/function. Different amino acid substitutions at the same codon (S502T/L) have been reported previously in association with Noonan syndrome (Maheshwari et al., 2002; Bertola et al, 2006; Tartaglia et al., 2006). Additionally, missense variants in nearby residues (R498W/L, R501K, G503R/V/A/E, M504V, Q506P, T507K) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret S502A as a pathogenic variant
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000033542 SCV000204035 pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome 2014-01-07 criteria provided, single submitter clinical testing The Ser502Ala variant in PTPN11 has been previously identified in 2 individuals with clinical features of Noonan syndrome, including in 1 individual where it wa s found to have occurred de novo and in 1 individual who developed juvenile myel omonocytic leukemia (JMML; Kratz 2005, Sakaguchi 2013). This variant has also be en identified in 1 individual with acute myeloid leukemia (AML; Tartaglia 2005). In addition, this variant is absent from large population studies. Three other amino acid changes at this location (Ser502Thr, Ser502Pro, Ser502Leu) have been associated with the clinical features of Noonan syndrome and/or LEOPARD syndrome , and have also been identified as somatic variants in individuals with hematolo gic malignancies (Tartaglia 2006, Goemans 2005, Paulsson 2007, Ko 2008, Aoki 200 8). In summary, this variant meets our criteria to be classified as pathogenic ( based upon de novo occurrence, absence from the g eneral population, and multiple additional pathogenic variants at this position.

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