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

dbSNP: rs397507531

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000077861	SCV000057413	pathogenic	not provided	2022-05-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often 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: 24183200, 28483241, 17339163, 17222357, 15689434, 34136918, 24803665, 26918529, 23771920, 22848035, 19120036, 15996221, 19303148, 11992261, 11704759, 17056636, 16523510, 12960218, 16124853, 18854871, 17020470, 16377799, 12717436, 18678287, 18470943, 27619028, 26297936, 26249544, 21533187, 21500339, 21396583, 19467855, 19206169, 9222968, 8530013, 1543375, 4025385, 1258892, 4386970, 30417923, 30050098, 29907801, 31219622, 31560489, 31324109, 32565546, 33300679, 34134972, 27521173, 29493581)
Eurofins Ntd Llc (ga)	RCV000077861	SCV000058296	pathogenic	not provided	2013-05-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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as well as Noonan-like/multiple giant-cell lesion syndrome ( Tartaglia 2002, Nystrom 2008, Jafarov 2005, Lee 2005, LMM unpublished data).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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231840	SCV000287696	pathogenic	RASopathy	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 285 of the PTPN11 protein (p.Phe285Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan or Noonan-like syndrome (PMID: 11992261, 15689434, 15996221, 23771920). ClinVar contains an entry for this variant (Variation ID: 40528). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 function. This variant disrupts the p.Phe285 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17339163, 18470943, 18678287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	RCV004018710	SCV000741101	pathogenic	Cardiovascular phenotype	2024-02-16	criteria provided, single submitter	clinical testing	The c.853T>C (p.F285L) alteration is located in exon 7 (coding exon 7) of the PTPN11 gene. This alteration results from a T to C substitution at nucleotide position 853, causing the phenylalanine (F) at amino acid position 285 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been described in multiple individuals with a clinical diagnosis of Noonan syndrome (Tartaglia, 2002; Chinton, 2019) and in other patients with Noonan syndrome-like features (Jafarov, 2005; Nyström, 2009). Another nucleotide substitution within the same codon, c.855T>G, has also been observed to result in p.F285L, and has also been described in multiple individuals with a clinical diagnosis of Noonan syndrome (Hung, 2007; Athota, 2020). Furthermore, additional alterations affecting amino acid residue F285 (p.F285C, p.F285S, p.F285I) have been described in individuals with Noonan syndrome (Tartaglia, 2006; Ferrero, 2008; Essawi, 2013). This amino acid position is highly conserved in available vertebrate species. The p.F285L amino acid is located in the protein tyrosine phosphatase (PTP) functional domain of the SHP-2 protein, and is predicted to disrupt the interdomain interaction with the N-SH2 domain, which normally stabilizes the inactive conformation of the protein (Tartaglia, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
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 Munich, Klinikum Rechts Der Isar, TU München	RCV000856809	SCV001430035	pathogenic	Noonan syndrome 1	2020-03-26	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288529	SCV002579789	pathogenic	LEOPARD syndrome 1	2021-12-15	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000856809	SCV003841263	pathogenic	Noonan syndrome 1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.76). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000040528) and different missense changes at the same codon (p.Phe285Cys, p.Phe285Ile, p.Phe285Ser, p.Phe285Tyr, p.Phe285Val / ClinVar ID: VCV000013335, VCV000040527, VCV000040533, VCV000181499, VCV000636408) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV000077861	SCV004703597	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PTPN11: PS1, PS2, PM2, PM5, PS4:Moderate, PP3
Baylor Genetics	RCV002288529	SCV005049705	pathogenic	LEOPARD syndrome 1	2023-12-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000856809	SCV005049789	pathogenic	Noonan syndrome 1	2023-12-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004562222	SCV005049870	pathogenic	Metachondromatosis	2023-12-06	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000856809	SCV005091067	pathogenic	Noonan syndrome 1	2024-02-07	criteria provided, single submitter	clinical testing	PS1, PS4, PM1, PM2, PP3, PP5 - Same amino acid change as a known pathogenic variant. Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. This variant has been previously reported as causative for Noonan syndrome. (PMID:32164556).
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000077861	SCV005197300	pathogenic	not provided	2022-05-27	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
PreventionGenetics, part of Exact Sciences	RCV004532490	SCV004723855	pathogenic	PTPN11-related disorder	2024-01-13	no assertion criteria provided	clinical testing	The PTPN11 c.853T>C variant is predicted to result in the amino acid substitution p.Phe285Leu. This variant has been reported in multiple individuals with Noonan Syndrome and in several cases it was determined to be de novo (see for examples Tartaglia et al. 2002. PubMed ID: 11992261; Nyström et al. 2009. PubMed ID: 19120036; van Trier et al. 2016. PubMed ID: 27521173). A different nucleotide substitution (c.855T>G) resulting in the same missense variant has been reported in multiple individuals with Noonan syndrome (Hung et al. 2007. PubMed ID: 17339163). Additionally, different missense variants affecting this amino acid (p.Phe285Ile, p.Phe285Val, p.Phe285Tyr, p.Phe285Ser, p.Phe285Cys) have been reported to be pathogenic (Ferrero et al. 2008. PubMed ID: 18678287; El Naofal et al. 2023. PubMed ID: 36703223; Yu et al. 2019. PubMed ID: 30896080; Tartaglia et al. 2002. PubMed ID: 11992261; Tartaglia et al. 2006. PubMed ID: 16358218). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been classified as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/40528). This variant is interpreted as pathogenic.