ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.218C>T (p.Thr73Ile) (rs121918462)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000156985 SCV000206707 pathogenic Noonan syndrome 2012-06-12 no assertion criteria provided clinical testing
Baylor Miraca Genetics Laboratories, RCV000033475 SCV000196660 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
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
GeneDx RCV000212891 SCV000057380 pathogenic not provided 2018-11-07 criteria provided, single submitter clinical testing The T73I missense variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2002), and has been observed to occur de novo in patients tested at GeneDx. It is the most common pathogenic variant found in infants with Noonan syndrome / Myeloproliferative disease (NS/MPD), having been identified in 8 out of 19 children studied (Kratz et al., 2005). This variant has also been reported in a single patient reported to have Noonan-like / multiple giant cell lesion syndrome (NS/MGCLS) (Bufalino et al., 2010). The T73I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). T73I is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that T73I results in increased activity compared to wild type (Keilhack et al., 2005). Missense variants in nearby residues (E69Q, F71I/L, A72P/S/G, E76V/G/D) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret T73I as a pathogenic variant.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000014262 SCV000143816 not provided Noonan syndrome 1 no assertion provided not provided
Integrated Genetics/Laboratory Corporation of America RCV000156985 SCV000053297 pathogenic Noonan syndrome 2015-04-03 no assertion criteria provided clinical testing
Invitae RCV000033475 SCV000821663 pathogenic Rasopathy 2018-05-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 73 of the PTPN11 protein (p.Thr73Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome (PMID: 11992261, 15240615, 17339163, 17020470) and has been reported to be de novo in several affected individuals (PMID: 20383758, 23446178). Additionally, this variant has been reported in several individuals affected with Noonan-syndrome associated myeloproliferative disorder and it has been reported that this variant carries a higher risk of developing hematological malignancies than other Noonan syndrome associated variants (PMID: 23832011, 14644997, 15928039). ClinVar contains an entry for this variant (Variation ID: 13334). Experimental studies have shown that this missense change functionally activates the Shp2 tyrosine phosphatase (PMID: 15987685). Additionally studies have shown that this variant leads to heart defects in zebrafish embryos (PMID: 24718990). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156985 SCV000200000 pathogenic Noonan syndrome 2016-10-12 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
OMIM RCV000014262 SCV000034510 pathogenic Noonan syndrome 1 2005-04-15 no assertion criteria provided literature only

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