ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1381G>T (p.Ala461Ser)

dbSNP: rs121918468
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033529 SCV000057434 pathogenic not provided 2014-02-08 criteria provided, single submitter clinical testing The A461S missense mutation in the PTPN11 gene has been reported previously in association with autosomal dominant LEOPARD syndrome (LS) (Osawa, 2009). The Alanine 461 codon lies in a PTP enzyme active site which is a mutational hotspot in PTPN11. A different mutation in the same codon, A461T, has been published in cases of LEOPARD syndrome (Kontaridis, 2005). Therefore, the presence of A461S is consistent with a diagnosis of LEOPARD syndrome. The variant is found in NOONAN panel(s).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037612 SCV000061273 pathogenic Noonan syndrome with multiple lentigines 2009-07-16 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000033529 SCV000928189 pathogenic not provided 2019-01-23 criteria provided, single submitter clinical testing
Invitae RCV001060541 SCV001225236 pathogenic RASopathy 2023-06-30 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala461 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15389709, 15470362, 16377799, 20493809, 23799168, 24718990, 24935154). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 40546). This missense change has been observed in individual(s) with PTPN11-related rasopathies and clinical features of NF1-Noonan syndrome (PMID: 19659470, 22465605, 24790373; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 461 of the PTPN11 protein (p.Ala461Ser).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV001729356 SCV001976665 pathogenic LEOPARD syndrome 1 2021-10-01 criteria provided, single submitter clinical testing PM1, PM2, PM5, PP2, PP3, PP5

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