ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.211T>C (p.Phe71Leu) (rs397507512)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033470 SCV000057375 pathogenic not provided 2017-03-22 criteria provided, single submitter clinical testing The F71L variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Musante et al., 2003). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The F71L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same (F71I) and in nearby residues (E69Q, A72S/P/G, T73I, E76V/A/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. Therefore, the presence of the F71L variant is consistent with the diagnosis of a RASopathy.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151689 SCV000199998 likely pathogenic Noonan syndrome 2013-04-05 criteria provided, single submitter clinical testing The Phe71Leu variant in PTPN11 has not been seen before in our laboratory; howev er it has been reported in the literature in clinical features of Noonan syndrom e and pediatric acute myeloid leukemia (AML; Musante 2003, Loh 2004, Chan 2006). The Phe71Leu variant has not been identified in large European American and Afr ican American populations by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS/). This variant has also been identified as an acquired somati c mutation in patients with hematological malignancies (Tartaglia 2006, Tartagli a 2005, Loh 2004, Chan 2006). The majority of identified pathogenic variants in the PTPN11 gene are located in exon 3 and involve the amino acids preceding and following the Phe71 residue, affect the N-SH2 domain, and are gain-of-function/a ctivating variants. Computational analyses (biochemical amino acid properties, c onservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for o r against an impact to the protein. In summary, this variant is likely pathogeni c, though additional studies are required to fully establish its clinical signif icance.
Integrated Genetics/Laboratory Corporation of America RCV000586528 SCV000698068 likely pathogenic Noonan syndrome 3 2017-03-27 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.211T>C (p.Phe71Leu) variant located in the N-SH2 domain involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest has not been observed in 121630 control chromosomes (ExAC and publication controls). Multiple publications have cited the variant in affected individuals diagnosed with Noonan syndrome, pediatric acute myeloid leukemia (AML) or JMML (Juvenile Myelomonocytic Leukemia). The variant of interest has also been indicated as a somatic occurrence in multiple patients with the Leukemic presentation(s). It is important to note that somatic PTPN11 mutations have been reported to exist in up to 35% of patients with JMML while germline PTPN11 mutations cause Noonan syndrome. Furthermore, additonal variants causing the same missense change, c.213T>A and c.213T>G, or another missense change at this position, c.211T>A (p.Phe71Ile) have been reported in the pathogenic spectrum, therefore, indicating the location is important for protein function. In addition, multiple clinical diagnostic laboratories classify the variant as "likely pathogenic/pathogenic." No well-established functional studies supportive of a damaging effect on the protein product have been published. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "likely pathogenic."
Invitae RCV000686123 SCV000813626 pathogenic Rasopathy 2018-06-11 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 71 of the PTPN11 protein (p.Phe71Leu). 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 observed in individuals affected with Noonan syndrome (PMID: 12634870, 25097206, 18759865, 19737548, Invitae), including at least one de novo observation,  and in an individual affected with myelodysplastic syndrome (PMID: 14644997). In addition, a different variant (c.211T>G) giving rise to the same protein effect observed here (p.Phe71Leu) has been reported in an individual affected with Noonan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 40499). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change is located in a region of the PTPN11 protein where a significant number of previously reported PTPN11 missense mutations are found (PMID: 18470943). These observations suggest that a missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000033470 SCV000884431 pathogenic not provided 2018-04-11 criteria provided, single submitter clinical testing The PTPN11 c.211T>C; p.Phe71Leu variant (rs397507512) has been reported as a germline variant in multiple individuals with Noonan syndrome (Musante 2003, Strullu 2014), and also as a somatic variant in cases of juvenile myeolmonocytic leukemia and related malignancies (Strullu 2014, Tartaglia 2003, Zhange 2011). This variant, like most PTPN11 pathogenic variants associated with Noonan syndrome and childhood malignancies, affects the N-terminal SH2 regulatory domain of the protein (Musante 2003), and multiple other variants affecting this amino acid and other nearby residues have also been reported as pathogenic, including p.Phe71Ile, p.Glu69Gln, p.Lys70Arg, and p.Ala72Gly (Niihori 2005, Musante 2003, Xu 2017, Tartaglia 2001). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and is classified as pathogenic/likely pathogenic in ClinVar (variant ID: 40499). Based on the available evidence, the p.Phe71Leu variant is classified as pathogenic.

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