Submissions for variant NM_002834.5(PTPN11):c.1472C>A (p.Pro491His)

dbSNP: rs397507540

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	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, Mass General Brigham Personalized 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, University Hospital Tübingen	RCV000033537	SCV001446672	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Invitae	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, 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