Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000033537 | SCV000057442 | pathogenic | not provided | 2019-05-16 | criteria provided, single submitter | clinical testing | The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17020470, 24803665, 17546245, 30417923, 31560489) |
Laboratory for Molecular Medicine, |
RCV000037617 | SCV000061279 | pathogenic | Noonan syndrome | 2015-09-29 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
Blueprint Genetics | RCV000033537 | SCV000927247 | pathogenic | not provided | 2017-05-04 | criteria provided, single submitter | clinical testing | |
Institute of Medical Genetics and Applied Genomics, |
RCV000033537 | SCV001446672 | likely pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001378165 | SCV001575676 | pathogenic | RASopathy | 2023-07-31 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro491 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15985475, 18470943, 20186801, 22781091, 23624134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40551). This missense change has been observed in individuals with Noonan syndrome (PMID: 17020470, 17546245, 21590266). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 491 of the PTPN11 protein (p.Pro491His). |
DASA | RCV001730478 | SCV001980673 | pathogenic | Short stature; Abnormal facial shape; Strabismus | 2021-09-02 | criteria provided, single submitter | clinical testing | The c.1472C>A;p.(Pro491His) variant has been published as a pathogenic variant in association with Noonan syndrome (PMID: 17546245, 21590266, 17020470; GeneOne, DASA) - PS4; ClinVar contains an entry for this variant (Variation ID: 40551); This variant is not present in population databases (rs397507540 - gnomAD no frequency; ABraOM no frequency - abraom.ib.usp.br) - PM2; Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PMID: 29493581) - PP2; In silico analysis predicts this variant is probably damaging to the protein structure/function - PP3; Pathogenic missense variants in this residue (PMID: 20186801, 18470943, 23624134). In summary, the currently available evidence indicates that the variant is pathogenic. |
Ambry Genetics | RCV002390130 | SCV002697983 | pathogenic | Cardiovascular phenotype | 2018-05-09 | criteria provided, single submitter | clinical testing | The p.P491H pathogenic mutation (also known as c.1472C>A), located in coding exon 13 of the PTPN11 gene, results from a C to A substitution at nucleotide position 1472. The proline at codon 491 is replaced by histidine, an amino acid with similar properties. This mutation was first described in an individual meeting clinical diagnostic criteria for Noonan syndrome (Bertola DR et al. Genet. Test., 2006;10:186-91). In addition, three disease-causing mutations: p.P491L, p.P491S, and p.P491T, have been described in the same codon (Binder G et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5377-81; Pierpont EI et al. Genes Brain Behav., 2009 Apr;8:275-82; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Fulgent Genetics, |
RCV002490446 | SCV002802840 | likely pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2021-11-09 | criteria provided, single submitter | clinical testing |