Submissions for variant NM_002834.5(PTPN11):c.214G>T (p.Ala72Ser)

dbSNP: rs121918453

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212890	SCV000057376	pathogenic	not provided	2022-08-02	criteria provided, single submitter	clinical testing	Identified in several patient patients with Noonan spectrum disorders referred for genetic testing at GeneDx and in published literature (Hakami et al., 2016); observed once apparently de novo; Published functional studies demonstrate a damaging effect; results in significantly increased tyrosine-phosphatase activity resulting in prolonged ligand-dependent ERK2 activation (Fragale et al., 2004; Oishi et al., 2006; Bocchinfuso et at., 2007); 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: 29907801, 30417923, 32164556, 16399795, 14974085, 11704759, 17177198, 24803665, 26918529, 30050098, 31560489, 33318624, 27535533, 32059087, 11992261, 9491886, 16053901, 29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000157001	SCV000061298	pathogenic	Noonan syndrome	2014-05-15	criteria provided, single submitter	clinical testing	The Ala72Ser variant has been reported in the literature in many individuals wit h clinical features of Noonan syndrome (Zenker 2004, Tartaglia 2006, Kosaki 2002 , Bocchinfuso 2007, Fragale 2004, Hung 2007, Limal 2006, Lo 2009, Martinelli 200 6, Musante 2003, Noordam 2008, Oishi 2006). Other variants at this position (Ala 72Thr, Ala72Val) have been observed as somatic changes in hematologic malignanci es, indicating the importance of this residue in normal function of the protein (Tartaglia 2005). In summary, this variant meets our criteria to be classified a s pathogenic (http://pcpgm.partners.org/LMM).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212890	SCV000206725	pathogenic	not provided	2023-09-11	criteria provided, single submitter	clinical testing	The PTPN11 c.214G>T; p.Ala72Ser variant (rs121918453) is reported in the literature in individuals affected with Noonan syndrome (Athota 2020, Chinton 2019, Hakami 2016, Kauffman 2021, Tartaglia 2001). This variant is also reported in ClinVar (Variation ID: 13324) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Val, Asp, Thr, and Gly) have been reported in individuals with Noonan syndrome or leukemia and are considered disease-causing (Tartaglia 2005, Tartaglia 2002). Functional analyses demonstrate increased tyrosine-phosphatase activity resulting in prolonged ERK2 activation (Bocchinfuso 2007, Fragale 2004, Oishi 2006). Computational analyses predict that this variant is deleterious (REVEL: 0.805). Based on available information, this variant is considered to be pathogenic. References: Athota JP et al. Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. BMC Med Genet. 2020 Mar 12;21(1):50. PMID: 32164556. Bocchinfuso G et al. Structural and functional effects of disease-causing amino acid substitutions affecting residues Ala72 and Glu76 of the protein tyrosine phosphatase SHP-2. Proteins. 2007 Mar 1;66(4):963-74. PMID: 17177198. 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. Fragale A et al. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat. 2004 Mar;23(3):267-77. PMID: 14974085. Hakami F et al. Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder. Prenat Diagn. 2016 May;36(5):418-23. PMID: 26918529. Kauffman H et al. Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines. Pediatr Res. 2021 Aug;90(2):444-451. PMID: 33318624. Oishi K et al. Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations. Hum Mol Genet. 2006 Feb 15;15(4):543-53. PMID: 16399795. Tartaglia M et al. Germ-line and somatic PTPN11 mutations in human disease. Eur J Med Genet. 2005 Apr-Jun;48(2):81-96. PMID: 16053901. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. PMID: 11992261.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000212890	SCV000511033	pathogenic	not provided	2016-10-17	criteria provided, single submitter	clinical testing
Invitae	RCV000033471	SCV000659045	pathogenic	RASopathy	2022-10-10	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 13324). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 14974085, 16399795). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 12161469, 17339163, 18678287, 26918529). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 72 of the PTPN11 protein (p.Ala72Ser).
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000576667	SCV000678222	pathogenic	Noonan syndrome 1; LEOPARD syndrome 1	2017-08-01	criteria provided, single submitter	clinical testing	PTPN11 NM_002834.3 exon3 p.Ala72Ser (c.214G>T): This variant has been reported in the literature in at least 8 individuals with a diagnosis or clinical suspicion of Noonan syndrome, segregating with disease in 3 affected family members (Tartaglia 2001 PMID:11704759, Koskai 2002 PMID:12161469, Musante 2003 PMID:12634870, Fragale 2004 PMID:14974085, Zenker 2004 PMID:15001945, Limal 2006 PMID:16263833, Martinelli 2006 PMID:16631468, Oishi 2006 PMID:16399795, Hung 2007 PMID:17339163, Noordam 2008 PMID:18562489, Lo 2010 PMID:19737548). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic. (Variation ID:13324). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant occurs within the N-SH2/PTP interaction domain, a critical region for the function of this gene, and increases the likelihood that this variant is damaging (Tartaglia 2002 PMID: 11992261. Strullu 2014 PMID:25097206). In summary, this variant is classified as pathogenic based on the data above (presence in affected probands, segregation studies, absence in controls, presence in critical region/impact to protein).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000033471	SCV000698070	pathogenic	RASopathy	2019-08-26	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.214G>T (p.Ala72Ser) results in a conservative amino acid change located in the first Src homology 2 (SH2) domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251856 control chromosomes (gnomAD and publication data). c.214G>T has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Tartaglia_2001, Kosaki_2002, Tartaglia_2006, Digilio_2013), in one of these publications the variant was reported to segregate with the disease in a family (Tartaglia_2001). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated the variant increased phosphatase activity under basal and stimulated conditions (Tartaglia_2006, Bocchinfuso_2007). Missense variants affecting the same residue (A72T, A72P, A72G) and nearby residues (F71I, F71L, T73I) have been reported in patients affected with Noonan syndrome (HGMD), suggesting these residues are critical for PTPN11 function. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762883	SCV000893271	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212890	SCV001746165	pathogenic	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000212890	SCV001762001	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813190	SCV002060906	pathogenic	Noonan syndrome and Noonan-related syndrome	2020-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000014252	SCV002540265	pathogenic	Noonan syndrome 1	2021-12-17	criteria provided, single submitter	clinical testing	The PTPN11 c.214G>T (p.Ala72Ser) missense variant results in the substitution of alanine at amino acid position 72 with serine. Across a selection of the available literature, this variant has been identified in a heterozygous state in at least six individuals with Noonan syndrome (Tartaglia et al. 2001; Kosaki et al. 2002; Musante et al. 2002; Noordam et al. 2006; Lazzaro et al. 2019). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. In vitro functional studies demonstrated that the p.Ala72Ser variant significantly increased PTPN11 phosphatase activity and prolonged ERK activation (Fragale et al. 2004). This variant was identified in a de novo state. Based on the available evidence, the c.214G>T (p.Ala72Ser) variant is classified as pathogenic for Noonan syndrome.
OMIM	RCV000014252	SCV000034500	pathogenic	Noonan syndrome 1	2002-08-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000033471	SCV000196659	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000212890	SCV001800278	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212890	SCV001955495	pathogenic	not provided		no assertion criteria provided	clinical testing