Submissions for variant NM_002834.5(PTPN11):c.1471C>T (p.Pro491Ser)

dbSNP: rs397507539

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254684	SCV000057441	pathogenic	not provided	2022-07-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant results in increased phosphatase activity of the SHP-2 protein (Edwards et al., 2014).; The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14982869, 24891296, 24803665, 27521173, 17020470, 28746941, 15985475, 19077116, 22465605, 30541462, 31560489, 29493581, 16358218, 15001945, 32737134, 27535533)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000157010	SCV000061277	pathogenic	Noonan syndrome	2020-09-02	criteria provided, single submitter	clinical testing	The p.Pro491Ser variant in PTPN11 has been identified in more than 10 individuals with clinical features of Noonan syndrome, including one individual in whom it occurred de novo (Bertola 2006 PMID: 17020470; Tartaglia 2006 PMID: 16358218; Yang 2018 PMID: 30541462; LMM data). This variant has also been identified as a somatic change occurring in an individual with acute lymphoblastic leukemia (Tartaglia 2004 PMID: 14982869). It has been identified in 0.001% (1/113754) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID 40550). Additionally, several other pathogenic changes (p.Pro491Thr; p.Pro491Leu; p.Pro491His) have been identified at this position, suggesting that this residue is critical to the function of the protein. In vitro functional studies support an impact on protein function (Edwards 2014 PMID: 24891296). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP codes applied: PS4, PM5_Strong, PM6, PS3_Supporting.
Invitae	RCV000033536	SCV000549982	pathogenic	RASopathy	2023-09-23	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, 19621452, 22465605). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function. ClinVar contains an entry for this variant (Variation ID: 40550). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 16358218, 17020470, 19077116, 22465605). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs397507539, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 491 of the PTPN11 protein (p.Pro491Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000033536	SCV000920099	pathogenic	RASopathy	2019-11-18	criteria provided, single submitter	clinical testing	Variant summary: Variant summary: PTPN11 c.1471C>T (p.Pro491Ser) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain and Tyrosine specific protein phosphatases domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found in 1/246860 control chromosomes, a frequency of 4.1e-06. c.1471C>T has been reported in the literature in numerous individuals affected with Noonan Syndrome or related disorders, indicating the variant is very likely to be associated with disease. In addition, several variants causing a change at the same codon have been reported as associated with Noonan Syndrome (p.P491A, p.P491H, p.P491L, p.P491T), suggesting the proline is critical for proper gene function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000984919	SCV000992411	pathogenic	Noonan syndrome 1		criteria provided, single submitter	case-control
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000157010	SCV001156694	pathogenic	Noonan syndrome	2019-06-26	criteria provided, single submitter	clinical testing	The PTPN11 c.1471C>T; p.Pro491Ser variant (rs397507539) is reported in the literature in multiple individuals affected with Noonan syndrome (Aoki 2008, Rasmussen 2008, Tartaglia 2006, van Trier 2016). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 40550). The proline at codon 491 is highly conserved, and functional assays suggest this variant causes increased phosphatase activity of the PTPN11 protein (Edwards 2014). Additionally, other amino acid substitutions at this codon (p.Pro491His, p.Pro491Leu, p.Pro491Phe) have been reported in individuals with Noonan syndrome and are considered disease-causing (Aoki 2008, Binder 2005, Schuettpelz 2009, Tartaglia 2006). Based on available information, the p.Pro491Ser 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. Binder G et al. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5377-81. Edwards JJ et al. A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype. Am J Med Genet A. 2014 Sep;164A(9):2351-5. Rasmussen KJ et al. Bile duct anomalies in a male child with Noonan syndrome: a case for ras and notch pathway synergism. Am J Med Genet A. 2008 Jan 15;146A(2):261-3. Schuettpelz LG et al. Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr Blood Cancer. 2009 Dec;53(6):1147-9. 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. van Trier DC et al. Ocular Manifestations of Noonan Syndrome: A Prospective Clinical and Genetic Study of 25 Patients. Ophthalmology. 2016 Oct;123(10):2137-46.
CeGaT Center for Human Genetics Tuebingen	RCV000254684	SCV001247469	pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813257	SCV002060562	pathogenic	Noonan syndrome and Noonan-related syndrome	2021-01-14	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000254684	SCV002501600	pathogenic	not provided	2021-12-27	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000254684	SCV002770732	pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000033536	SCV000196652	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000984919	SCV001132827	pathogenic	Noonan syndrome 1	2019-01-29	no assertion criteria provided	clinical testing