Submissions for variant NM_002834.5(PTPN11):c.124A>G (p.Thr42Ala)

dbSNP: rs397507501

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157675	SCV000057355	pathogenic	not provided	2022-06-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant increase in phosphopeptide binding affinity without greatly altering binding specificity or secondary structure of the domain (Keilhack et al., 2005; Muller et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16358218, 30417923, 30050098, 18372317, 23584145, 15987685, 25425531, 24803665, 21590266, 17661820, 28483241, 11992261, 22781091, 29988639, 29907801, 31219622, 31560489, 32164556, 31936901, 32668055, 29493581, 33258288, 32786180)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000157002	SCV000061270	pathogenic	Noonan syndrome	2013-01-25	criteria provided, single submitter	clinical testing	The Thr42Ala variant in PTPN11 has been reported in 10 individuals in the litera ture (Tartaglia 2002, Sarkozy 2003, Zenker 2004, Lee 2007, Shaw 2007, Martinelli 2008, Digilio 2012) and one individual in our laboratory with clinical features of Noonan syndrome. This variant was reported to have occurred de novo in at le ast one of these individuals (Digilio 2012). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Blueprint Genetics	RCV000157002	SCV000264157	pathogenic	Noonan syndrome	2015-06-19	criteria provided, single submitter	clinical testing
Invitae	RCV000227194	SCV000287692	pathogenic	RASopathy	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 42 of the PTPN11 protein (p.Thr42Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 15001945, 16358218, 17661820, 21590266, 22781091). ClinVar contains an entry for this variant (Variation ID: 40482). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 18372317, 23584145). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000227194	SCV001361724	pathogenic	RASopathy	2019-03-25	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.124A>G (p.Thr42Ala) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246614 control chromosomes (gnomAD). c.124A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome, including de novo cases (Tartaglia_2002, Sarkozy_2003, Zenker_2004, Lee_2007, VanTrier_2015, Tamura_2018, Ezquieta_2012). These data indicate that the variant is very likely to be associated with disease. This variant exhibits increased affinity for mono-Tyr(P) peptide and phosphopeptide (Keilhack_2005 and Martinelli_2008), which is believed to be one of the mechanisms of SHP2's functional dysregulation. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001330777	SCV001522569	pathogenic	Noonan syndrome 1	2020-06-03	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813241	SCV002060946	pathogenic	Noonan syndrome and Noonan-related syndrome	2018-12-01	criteria provided, single submitter	clinical testing
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV001330777	SCV002578151	pathogenic	Noonan syndrome 1	2022-09-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399352	SCV002669239	pathogenic	Cardiovascular phenotype	2019-10-24	criteria provided, single submitter	clinical testing	The p.T42A pathogenic mutation (also known as c.124A>G), located in coding exon 2 of the PTPN11 gene, results from an A to G substitution at nucleotide position 124. The threonine at codon 42 is replaced by alanine, an amino acid with similar properties, and is located in the N-SH2 domain. This mutation has been reported in numerous individuals with Noonan syndrome, including at least two reportedly de novo cases (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74; Lee ST et al. Clin. Genet., 2007 Aug;72:150-5; van Nierop JWI et al. Int. J. Pediatr. Otorhinolaryngol., 2017 Jun;97:228-234). Functional studies showed increased phosphopeptide binding affinity and dephosphorylation (Martinelli S et al. Hum. Mol. Genet., 2008 Jul;17:2018-29). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002482941	SCV002785167	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-09-17	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV001330777	SCV003841251	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.124A>G in Exon 2 of the PTPN11 gene that results in the amino acid substitution p.Thr42Ala was identified. The observed variant has a minor allele frequency of 0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. This variant has previously reported for patients with RASopathies by Digilio MC, et, al., 2012. Functional studies showed increased phosphopeptide binding affinity and dephosphorylation (Martinelli S et al.,2008.) ClinVar has also classified this variant as Pathogenic (Variant ID: 40482). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
New York Genome Center	RCV001330777	SCV005044098	pathogenic	Noonan syndrome 1	2021-11-12	criteria provided, single submitter	clinical testing	The de novo c.124A>G (p.Thr42Ala) variant identified in the PTPN11 gene substitutes a moderatley conserved Threonine for Alanine at amino acid 42/594 (exon 2/16). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. The variant is predicted deleterious by multiple in silico prediction tools (CADD score = 25.3, REVEL score = 0.794). This variant is reported in ClinVar as Pathogenic (VarID: 40482), and has been reported in many individuals in the literature with Noonan syndrome [PMID:11992261, 15001945, 12960218, 29988639, 31560489, other]. Functional studies suggest that the p.Thr42Ala variant promotes increased phosphopeptide-binding affinity [PMID:18372317]. Given its presence de novo, absence in population databases, presence in multiple affected individuals in the literature, and functional studies suggesting a significant increase in phosphopeptide binding affinity, the c.124A>G (p.Thr42Ala) variant identified in the PTPN11 gene is reported as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000157002	SCV000206726	pathogenic	Noonan syndrome	2012-01-27	no assertion criteria provided	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157675	SCV000207646	pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing
Molecular Genetics, Centre for Human Genetics	RCV001330777	SCV004190080	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing