ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.598A>T (p.Asn200Tyr) (rs727503381)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151696 SCV000200010 pathogenic Noonan syndrome 2015-01-08 criteria provided, single submitter clinical testing The p.Asn200Tyr variant in PTPN11 has been reported in one individual with Noona n syndrome and multiple giant cell lesions and in her mother with Noonan syndrom e without multiple giant cell lesions (Carapito 2014). This variant was reported to have occurred de novo in the proband's mother. It has also been identified i n two individuals with clinical features of Noonan syndrome by our laboratory. T his variant was absent from large population studies. In summary, this variant m eets our criteria to be classified as pathogenic (http://www.partners.org/person alizedmedicine/LMM).
GeneDx RCV000380092 SCV000329774 likely pathogenic not provided 2016-04-26 criteria provided, single submitter clinical testing The N200Y variant has been previously confirmed as de novo in a patient with Noonan syndrome (Carapito et al., 2014). 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. N200Y is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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. Therefore, this variant is likely pathogenic.
Invitae RCV000654965 SCV000776875 likely pathogenic Rasopathy 2018-04-01 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 200 of the PTPN11 protein (p.Asn200Tyr). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to occur de novo in an individual affected with Noonan syndrome, and it was also found in the affected daughter (PMID: 24225993). ClinVar contains an entry for this variant (Variation ID: 164998). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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