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

dbSNP: rs397507540

Total submissions: 9

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378165	SCV001575676	pathogenic	RASopathy	2024-12-24	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PTPN11-related conditions and/or Noonan syndrome (PMID: 17020470, 17546245, 21590266, 31560489, 37923938). ClinVar contains an entry for this variant (Variation ID: 40551). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. 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. For these reasons, this variant has been classified as Pathogenic.
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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000033537	SCV005875608	pathogenic	not provided	2024-06-10	criteria provided, single submitter	clinical testing	The PTPN11 c.1472C>A; p.Pro491His variant (rs397507540, ClinVar Variation ID: 40551) is reported in the literature in numerous individuals affected with Noonan syndrome (selected references: Aoki 2008, Bessis 2019, Chinton 2019, Papadopoulos 2022). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Ser, Leu, Thr, Phe) have been reported in individuals with Noonan syndrome and are considered pathogenic (Aoki 2008, Ezquieta 2012, Jongmans 2011, Pierpont 2010, Tartaglia 2006).) Computational analyses predict that this variant is deleterious (REVEL: 0.756). Based on available information, this variant is considered to be pathogenic. References: Aoki Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008 Aug;29(8):992-1006. PMID: 18470943. Bessis D et al. Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation. Br J Dermatol. 2019 Jun;180(6):1438-1448. PMID: 30417923. Chinton J et al. Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina. Arch Argent Pediatr. 2019 Oct 1;117(5):330-337. English, Spanish. PMID: 31560489. Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 May;65(5):447-55. PMID: 22465605. Jongmans MC et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260. Papadopoulos G et al. Molecular and clinical profile of patients referred as Noonan or Noonan-like syndrome in Greece: a cohort of 86 patients. Eur J Pediatr. 2022 Oct;181(10):3691-3700. PMID: 35904599. Pierpont EI et al. Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. Am J Med Genet A. 2010 Mar;152A(3):591-600. PMID: 20186801. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218.