ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.853T>C (p.Phe285Leu) (rs397507531)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000077861 SCV000057413 pathogenic not provided 2017-10-26 criteria provided, single submitter clinical testing The F285L missense variant in the PTPN11 gene has been reported previously in association with autosomal dominant Noonan syndrome including instances of de novo occurrences (Tartaglia et al., 2002; Lee et al., 2005; Nystrom et al., 2009). This variant is not observed in large population cohorts (Lek et al., 2016). F285L is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties; however, this substitution occurs at a position in the highly conserved PTP domain of the gene, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (F285I/S/C), in a nearby residue (I282V/M), and a different nucleotide change leading to the same missense variant, c.855T>G, have been reported in the Human Gene Mutation Database in association with RASopathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret this as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077861 SCV000058296 pathogenic not provided 2013-05-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037662 SCV000061324 pathogenic Noonan syndrome 2012-06-26 criteria provided, single submitter clinical testing The p.Phe285Leu variant in PTPN11 has been associated with the clinical features of Noonan syndrome as well as Noonan-like/multiple giant-cell lesion syndrome ( Tartaglia 2002, Nystrom 2008, Jafarov 2005, Lee 2005, LMM unpublished data). Thi s variant has been observed to have occurred de novo in sporadic cases of Noonan syndrome. Furthermore, a different nucleotide substitution, c.855T>G, that resu lts in the same amino acid change has been identified in a sporadic case of Noon an syndrome (Hung 2007). Therefore, this variant meets our criteria to be classi fied as pathogenic.
Invitae RCV000231840 SCV000287696 pathogenic Rasopathy 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 285 of the PTPN11 protein (p.Phe285Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan or Noonan-like syndrome (PMID: 11992261, 23771920, 15689434, 15996221). ClinVar contains an entry for this variant (Variation ID: 40528). A different variant (c.855T>G) giving rise to the same protein effect observed here (p.Phe285Leu), as well as several other variants that result in different amino acid substitutions at this codon (p.Phe285Cys, p.Phe285Ser, p.Phe285Ile) have been reported in individuals affected with Noonan syndrome (PMID: 17339163, 18470943, 18678287), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000586058 SCV000698082 pathogenic Noonan syndrome 3 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.853T>C (p.Phe285Leu) variant involves the alteration of a conserved nucleotide at the end of the exon 7. 3/4 in silico tools predict a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. There are no published functional studies for this variant. However, this variant is located in the PTP domain (InterPro), which is known to be important for protein function. This variant is absent in 118444 control chromosomes and is reported as a pathogenic variant found in several patients with NS or NS-related syndrome. It has also been reported as a de novo variant multiple instances. A different nucleotide substitution, c.855T>G, that results in the same amino acid change has been identified in a sporadic case of Noonan syndrome (Hung_JFMA_2007) and is classified as pathogenic by two labs in ClinVar. In addition, other substitutions (F285C, F285I and F285S) have been reported at this codon in association with Noonan syndrome (Tartaglia et al., 2006; Ferrero et al., 2008; Tartaglia et al., 2002). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Disease Variant/Pathogenic.
Ambry Genetics RCV000623706 SCV000741101 likely pathogenic Inborn genetic diseases 2015-10-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000077861 SCV000884434 pathogenic not provided 2018-01-29 criteria provided, single submitter clinical testing The PTPN11 c.853T>C; p.Phe285Leu variant (rs397507531) is reported in the literature in individuals affected with Noonan or Noonan-like syndrome (Ferrero 2008, Jafarov 2005, Tartaglia 2002). This variant is reported as pathogenic five times in ClinVar (Variation ID: 40528) and is absent from the general population (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Another variant, c.855T>G, which results in the same amino acid change at codon 285, has also been reported in individuals affected with Noonan syndrome (Hung 2007). The phenylalanine at codon 285 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be deleterious. Additional variants resulting in different amino acid changes at this codon (Phe285Cys, Phe285Ile, Phe285Ser) have also been reported in individuals with Noonan syndrome (Aoki 2008, Ferrero 2008, Hung 2007), suggesting a critical role for this residue in protein function. Based on the above information, this variant is considered pathogenic. References: Aoki Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008 Aug;29(8):992-1006. Ferrero G et al. Clinical and molecular characterization of 40 patients with Noonan syndrome. Eur J Med Genet. 2008;51(6):566-72. Hung C et al. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc. 2007 Feb;106(2):169-72. Jafarov T et al. Noonan-like syndrome mutations in PTPN11 in patients diagnosed with cherubism. Clin Genet. 2005 Aug;68(2):190-1. 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.
Fulgent Genetics,Fulgent Genetics RCV000762885 SCV000893273 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856809 SCV000999376 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000856809 SCV001430035 pathogenic Noonan syndrome 1 2020-03-26 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000077861 SCV000207657 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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