Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
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, |
RCV001729356 | SCV001976665 | pathogenic | LEOPARD syndrome 1 | 2021-10-01 | criteria provided, single submitter | clinical testing | PM1, PM2, PM5, PP2, PP3, PP5 |