Submissions for variant NM_002834.5(PTPN11):c.1505C>T (p.Ser502Leu)

dbSNP: rs397507544

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033544	SCV000057449	pathogenic	not provided	2022-05-18	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: 28628100, 28084675, 24030381, 18948947, 17910045, 15385933, 28183348, 26918529, 18470943, 17020470, 16358218, 19020799, 24803665, 28991257, 30050098, 30287924, 29907801, 32164556, 31115076, 33318624, 29493581, 32368696)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037619	SCV000061281	pathogenic	Noonan syndrome	2013-01-15	criteria provided, single submitter	clinical testing	The Ser502Leu variant has been reported in the literature in two individuals wit h clinical features of Noonan syndrome and/or LEOPARD syndrome (Tartaglia 2006, Ko 2008). Our laboratory has identified this variant in one proband where parent al testing was performed and showed the variant occurred de novo (LMM unpublishe d data). This variant has also been identified as a somatic variant in individua ls with hematologic malignancies including AML and ALL (Goemans 2005, Paulsson 2 007). In addition, three other amino acid changes at this location (Ser502Thr, Ser502Pro, Ser502Ala) have been associated with the clinical features of Noonan syndrome and have also been identified as somatic variants in individuals with h ematologic malignancies (Aoki 2008). The Ser502 residue is conserved across spec ies and computational analyses (biochemical amino acid properties, AlignGVGD, Po lyPhen2, and SIFT) suggest that the Ser502Leu variant may impact the normal func tion of the protein. In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM) based upon the de novo occurrenc e combined with available published literature.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781773	SCV000920091	pathogenic	RASopathy	2021-05-31	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.1505C>T (p.Ser502Leu) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, there are several variants associated with disease at the same codon or surrounding codons (e.g., S502A, S502T, R501K, and G503A), suggesting the region is important for protein function. Serine at position 502 interacts with Glutamate at position 76 in the SH2 domain, leading to autoinhibition of PTPN11, and mutational hotspot variants at Serine 502 or Glutamate 76 were shown to activate PTPN11 (example, Chan_2007, PMID 17053061). The variant was absent in 252092 control chromosomes. c.1505C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome (example, Tartaglia_2006, Bertola_2006, Ezquieta_2012, Strullu_2014, Ko_2008, O'Halloran_2017). At-least one report of a reportedly de-novo occurrence was ascertained in the context of this evaluation (Ezquieta_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Two 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 (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000781773	SCV000936668	pathogenic	RASopathy	2022-07-12	criteria provided, single submitter	clinical testing	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, 15928039, 18470943, 23832011, 26242988, 27521173). 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: 40557). This missense change has been observed in individuals with Noonan syndrome or LEOPARD syndrome (PMID: 17020470, 19020799). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 502 of the PTPN11 protein (p.Ser502Leu).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002227049	SCV003921859	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing	- Variant is absent from gnomAD (both v2 and v3). - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Both the p.(Ser502Ala) and the p.(Ser502Thr) variants have been previously reported in patients with Noonan syndrome (ClinVar, PMID: 18470943, PMID: 11992261). - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Noonan syndrome (ClinVar, PMID: 18470943, PMID: 11992261, PMID: 28084675 and PMID: 32164556). - This variant has been shown to be de novo in the proband (parental status confirmed) by trio analysis. Additional information: - Both loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMID: 11992261, PMID: 24935154 and PMID: 21533187). - This variant is heterozygous. - This gene is associated with autosomal dominant disease. - Variant is predicted to result in a missense amino acid change from serine to leucine.
CeGaT Center for Human Genetics Tuebingen	RCV000033544	SCV004033226	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PTPN11: PS2:Very Strong, PM2, PM5, PP3
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000033544	SCV001740219	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000033544	SCV001953570	pathogenic	not provided		no assertion criteria provided	clinical testing
Prenatal Genetic Diagnosis Laboratory, The Chinese University of Hong Kong	RCV002227049	SCV002498740	pathogenic	Noonan syndrome 1	2021-07-22	no assertion criteria provided	clinical testing	This variant c.1505C>T(p.S502L) has been reported in multiple unrelated pateints with Noonan spectrum disorders [PMID: 22465605, 17020470, 32164556, 26918529, 28991257, 24803665, 29907801, 15385933, 30287924] and was reported to be de novo in at least one case (PS2). Missense variants in the same residue and nearby residues have been reported in multiple individuals with Noonan spectrum disorders (PMID: 16358218, 26242988, 23832011) (PM1). This variant is currently absent in the gnomAD database (PM2). Computational evidence support a deleterious effect on the gene product (PP3). This variant has been classified as pathogenic by multiple labs in ClinVar [Variation ID: 40557] (PP5). This variant is interpreted as pathogenic according to ACMG/AMP guidelines.