ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.214G>C (p.Ala72Pro) (rs121918453)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033472 SCV000057377 pathogenic not provided 2019-11-25 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12717436, 15928039, 26918529, 30355600, 18759865)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037635 SCV000061297 likely pathogenic Noonan syndrome 2012-09-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588856 SCV000698069 likely pathogenic Noonan syndrome 3 2017-01-30 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.214G>C (p.Ala72Pro) variant involves the alteration of a conserved nucleotide and is located at SH2 domain of the protein. 4/4 in silico tools predict damaging outcome for this variant. This variant is absent in 121394 control chromosomes from ExAC. PTPN11 p.Ala72Ser variant has been classified as pathogenic for NS phenotype by our laboratory and p.Ala72Thr as possibly pathogenic for JMML/ALL phenotype. Other pathogenic/potentially pathogenic variants at the same residue reported in ClinVar are p.Ala72Gly and p.Ala72Val. Thus, codon p.Ala72 is a mutational hot-spot. This variant has been reported as a germline mutation in two cases with clinical features of Noonans syndrome (Lee_2008, Hakami_2016) and as a somatic mutation in one case with acute monocytic/monoblastic leukemia (Liu_2016). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is currently classified as likely pathogenic.
Blueprint Genetics RCV000033472 SCV000927439 pathogenic not provided 2017-10-16 criteria provided, single submitter clinical testing

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