Submissions for variant NM_002834.5(PTPN11):c.1504T>A (p.Ser502Thr)

dbSNP: rs121918458

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212897	SCV000057448	pathogenic	not provided	2023-01-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant increase in phosphatase activity compared wildtype (Niihori et al., 2005); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 16358218, 15240615, 27521173, 12739139, 34184824, 12325025, 24803665, 15834506, 21407260, 25862627, 19737548, 32164556)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000014260	SCV000782254	pathogenic	Noonan syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000156995	SCV000884432	pathogenic	Noonan syndrome	2018-01-22	criteria provided, single submitter	clinical testing	The p.Ser502Thr variant (rs121918458) has been reported in multiple patients diagnosed with Noonan syndrome (Niihori 2005, Tartaglia 2006, van Trier 2016, Yoshida 2004), and reported as a presumed de-novo variant (Joyce 2016, Kondoh 2003, Maheshwari 2002). The serine residue is located in the phospho-tyrosine phosphatase domain of PTPN11, and interacts with the N-SH2 domain to mediate regulatory inhibition (Hof 1998). Functional characterization of the p.Ser502Thr protein indicates increased catalytic activity of the phosphatase (Niihori 2005), consistent with the established disease mechanisms of Noonan syndrome.
Blueprint Genetics	RCV000212897	SCV000927150	pathogenic	not provided	2017-02-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000014260	SCV001522570	pathogenic	Noonan syndrome 1	2019-11-18	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851849	SCV002235814	pathogenic	RASopathy	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 502 of the PTPN11 protein (p.Ser502Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 12325025, 32164556). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13332). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. This variant disrupts the p.Ser502 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12325025, 15928039, 17020470, 18470943, 19020799, 27521173). 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.
Fulgent Genetics, Fulgent Genetics	RCV002490364	SCV002787910	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-10-27	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000014260	SCV004806769	pathogenic	Noonan syndrome 1	2024-03-26	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000212897	SCV005197308	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004984639	SCV005478396	pathogenic	Cardiovascular phenotype	2024-11-14	criteria provided, single submitter	clinical testing	The c.1504T>A (p.S502T) alteration is located in exon 13 (coding exon 13) of the PTPN11 gene. This alteration results from a T to A substitution at nucleotide position 1504, causing the serine (S) at amino acid position 502 to be replaced by a threonine (T). for PTPN11-related RASopathy; however, it is unlikely to be causative of metachondromatosis. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with PTPN11-related RASopathy, including multiple cases of reported de novo occurrence (Maheshwari, 2002; Yoshida, 2004; Tartaglia, 2006; van Trier, 2015; Athota, 2020; Orlova, 2024). Two other alterations at the same codon, c.1505C>T (p.S502L) and c.1504T>G (p.S502A), have been reported in association with PTPN11-related RASopathy (Bertola, 2006; Joyce, 2016). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000014260	SCV000034508	pathogenic	Noonan syndrome 1	2003-07-01	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000033543	SCV000204062	pathogenic	Juvenile myelomonocytic leukemia; Noonan syndrome	2015-09-29	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
PreventionGenetics, part of Exact Sciences	RCV004532342	SCV004752008	pathogenic	PTPN11-related disorder	2024-01-19	no assertion criteria provided	clinical testing	The PTPN11 c.1504T>A variant is predicted to result in the amino acid substitution p.Ser502Thr. This variant has been reported in at least eight unrelated individuals with Noonan syndrome (Maheshwari et al. 2002. PubMed ID: 12325025; van Trier et al. 2016. PubMed ID: 27521173; Athota et al. 2020. PubMed ID: 32164556) and has been shown to be a de novo event in two cases (Maheshwari et al. 2002. PubMed ID: 12325025). Additionally, different amino acid substitutions (p.Ser502Ala, p.Ser502Leu) affecting the same amino acid have been reported as pathogenic (Kratz et al. 2005. PubMed ID: 15928039; Bertola et al. 2006. PubMed ID: 17020470). This variant has been interpreted as pathogenic by multiple clinical labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13332/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.