Submissions for variant NM_002834.5(PTPN11):c.1504T>G (p.Ser502Ala)

dbSNP: rs121918458

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212898	SCV000057447	pathogenic	not provided	2022-01-24	criteria provided, single submitter	clinical testing	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: 23832011, 24803665, 15928039, 26242988, 15842656, 16358218, 31263281, 22465605, 18470943)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000033542	SCV000204035	pathogenic	Juvenile myelomonocytic leukemia; Noonan syndrome	2014-01-07	criteria provided, single submitter	clinical testing	The Ser502Ala variant in PTPN11 has been previously identified in 2 individuals with clinical features of Noonan syndrome, including in 1 individual where it wa s found to have occurred de novo and in 1 individual who developed juvenile myel omonocytic leukemia (JMML; Kratz 2005, Sakaguchi 2013). This variant has also be en identified in 1 individual with acute myeloid leukemia (AML; Tartaglia 2005). In addition, this variant is absent from large population studies. Three other amino acid changes at this location (Ser502Thr, Ser502Pro, Ser502Leu) have been associated with the clinical features of Noonan syndrome and/or LEOPARD syndrome , and have also been identified as somatic variants in individuals with hematolo gic malignancies (Tartaglia 2006, Goemans 2005, Paulsson 2007, Ko 2008, Aoki 200 8). In summary, this variant meets our criteria to be classified as pathogenic ( http://pcpgm.partners.org/LMM) based upon de novo occurrence, absence from the g eneral population, and multiple additional pathogenic variants at this position.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212898	SCV000884429	pathogenic	not provided	2017-05-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212898	SCV001713606	pathogenic	not provided	2020-09-02	criteria provided, single submitter	clinical testing	PS4, PM6_Strong, PM5, PM2, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731329	SCV001983560	pathogenic	RASopathy	2021-09-25	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.1504T>G (p.Ser502Ala) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Other amino acid changes at this location (Ser502Thr, Ser502Ala, Ser502Leu) have been associated with the clinical features of Noonan syndrome and/or LEOPARD syndrome suggesting that Ser 502 is a critical amino acid essential for protein function (Tartaglia_2006). The variant was absent in 252116 control chromosomes. c.1504T>G has been reported in the literature as a de-novo germline variant in multiple individuals affected with Noonan Syndrome and related disorders as well as a somatic variant in settings of myelodysplastic related acute myeloid leukaemia (example, Kratz_2005, Tartaglia_2005, Tartaglia_2006, Kamisago_2005, Sakaguchi_2013, Ezquieta_2012, Joyce_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000212898	SCV002019555	pathogenic	not provided	2020-02-12	criteria provided, single submitter	clinical testing
Invitae	RCV001731329	SCV004296234	pathogenic	RASopathy	2023-03-08	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Noonan syndrome and/or PTPN11-related conditions (PMID: 15928039, 26242988). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. 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, 17020470, 19020799, 32164556). 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: 40556). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 502 of the PTPN11 protein (p.Ser502Ala).