Submissions for variant NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile)

dbSNP: rs121918462

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000156985	SCV000053297	pathogenic	Noonan syndrome	2019-04-06	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.218C>T (p.Thr73Ile) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276806 control chromosomes. c.218C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Juvenile Myelomonocyttic Leukema (JMML) (Tartaglia_2002, Tartaglia_2003, Niihori_2005, Kratz_2005, Kosaki_2002, Jongmans_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in enhanced phosphatase activity of mutant SHP-2. Five 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.
GeneDx	RCV000212891	SCV000057380	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	Identified in patients with Noonan spectrum disorders in published literature (Tartaglia et al., 2002; Kratz et al., 2005); Published functional studies demonstrate the variant results in increased activity compared to wild type (Keilhack et al., 2005); Not observed at significant frequency 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: 35050212, 34850017, 32164556, 23832011, 23446178, 24803665, 24718990, 26286251, 15928039, 20383758, 30355600, 28106910, 26918529, 30050098, 30378271, 29907801, 31219622, 31560489, 32144894, 32901917, 28191889, 35792504, 34974531, 11992261, 9491886, 29493581, 16053901, 15987685)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156985	SCV000200000	pathogenic	Noonan syndrome	2016-10-12	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000212891	SCV000511497	pathogenic	not provided	2016-10-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515312	SCV000611305	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2017-05-18	criteria provided, single submitter	clinical testing
Invitae	RCV000033475	SCV000821663	pathogenic	RASopathy	2023-07-25	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome, Noonan-syndrome associated myeloproliferative disorder (PMID: 11992261, 14644997, 15240615, 15928039, 17020470, 17339163, 20383758, 23446178, 23832011). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13334). 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. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 24718990). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 73 of the PTPN11 protein (p.Thr73Ile).
Baylor Genetics	RCV000014262	SCV001522576	pathogenic	Noonan syndrome 1	2022-11-01	criteria provided, single submitter	clinical testing
3billion	RCV000014262	SCV002012113	pathogenic	Noonan syndrome 1	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000013334.14, PMID: 25097206, 23446178, and 20383758, PS2, PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Thr73Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000044604.2, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.956, 3Cnet: 0.996, PP3). Patient's phenotype is considered compatible with Noonan syndrome (3billion dataset, PP4).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000212891	SCV002019557	pathogenic	not provided	2019-09-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813199	SCV002060928	pathogenic	Noonan syndrome and Noonan-related syndrome	2021-05-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415414	SCV002725347	pathogenic	Cardiovascular phenotype	2016-04-01	criteria provided, single submitter	clinical testing	The p.T73I pathogenic mutation (also known as c.218C>T), located in coding exon 3 of the PTPN11 gene, results from a C to T substitution at nucleotide position 218. The threonine at codon 73 is replaced by isoleucine, an amino acid with similar properties. This mutation has been described in the literature in multiple individuals with Noonan syndrome (Tartaglia M, Am. J. Hum. Genet. 2002 Jun; 70(6):1555-63; Kosaki K, J. Clin. Endocrinol. Metab. 2002 Aug; 87(8):3529-33) as well as in Noonan patients with accompanying Myeloproliferative disorders (MPD) or Juvenile myelomonocytic leukemia (JMML) (Kratz CP, Blood 2005 Sep; 106(6):2183-5. T; Niihori T, J. Hum. Genet. 2005; 50(4):192-202). This alteration has also been reported as a somatic mutation in individuals with hematologic malignancies (Tartaglia M, Am. J. Hum. Genet. 2006 Feb; 78(2):279-90). In addition, functional studies have shown a statistically significant increase in phosphatase activity in cells expressing the p.T73I mutation, when compared to wild-type (Niihori T, J. Hum. Genet. 2005; 50(4):192-202; Tartaglia M, Am. J. Hum. Genet. 2006 Feb; 78(2):279-90). Based on the supporting evidence, p.T73I is interpreted as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV000212891	SCV002821737	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	PTPN11: PM1, PM2, PS3:Moderate, PS4:Moderate, PP2, PP3
Baylor Genetics	RCV003147287	SCV003835334	pathogenic	Metachondromatosis	2022-11-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147288	SCV003835870	pathogenic	LEOPARD syndrome 1	2022-11-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000014262	SCV004098990	pathogenic	Noonan syndrome 1	2023-10-27	criteria provided, single submitter	clinical testing	This heterozygous mis-sense variant is identified in a 3 month male with congenital heart disease, facial dysmorphism, FTT, juvenial myelomonocytic leukemia and echogenic kidney. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [REVEL=0.95] predicts deleterious nature of this variant [PP3: Strong]. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 13334] with “conflicting interpretation of pathogenicity, ”Pathogenic (14); Uncertain Significance (1)” interpretation by multiple submitter [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic".
OMIM	RCV000014262	SCV000034510	pathogenic	Noonan syndrome 1	2005-04-15	no assertion criteria provided	literature only
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	RCV000014262	SCV000143816	not provided	Noonan syndrome 1		no assertion provided	not provided
Baylor Genetics	RCV000033475	SCV000196660	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000156985	SCV000206707	pathogenic	Noonan syndrome	2012-06-12	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212891	SCV001743328	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212891	SCV001953497	pathogenic	not provided		no assertion criteria provided	clinical testing