ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1678C>T (p.Leu560Phe) (rs397516797)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000159057 SCV000616409 likely benign Rasopathy 2017-04-03 reviewed by expert panel curation The c.1678C>T (p.Leu560Phe) variant in PTPN11 has been identified in individuals with some features of a RASopathy but none were diagnosed with a RASopathy (PS4 not met; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data; GTR ID's: 28338, 26957, 21766; SCV000061285.5; SCV000208999.2; SCV000207690.1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data: GTR ID: 26957; SCV000208999.2). In vitro functional studies provide some evidence that the p.Leu560Phe variant does not impact protein function (BS3; PMID: 15987685). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS3, BP5.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037623 SCV000061285 uncertain significance not specified 2009-01-27 criteria provided, single submitter clinical testing
GeneDx RCV000159057 SCV000208999 likely benign Rasopathy 2019-02-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Fulgent Genetics,Fulgent Genetics RCV000515375 SCV000611506 uncertain significance Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-23 criteria provided, single submitter clinical testing
Invitae RCV000159057 SCV000815176 uncertain significance Rasopathy 2019-04-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 560 of the PTPN11 protein (p.Leu560Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs397516797, ExAC 0.03%). This variant has been reported in an individual affected with Noonan syndrome and congenital hypertrophic cardiomyopathy (PMID: 12960218). ClinVar contains an entry for this variant (Variation ID: 44599). Experimental studies have shown that this missense change does not affect basal and enzymatic activity (PMID: 15987685). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000988918 SCV001138831 likely benign Metachondromatosis 2019-05-28 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157702 SCV000207690 uncertain significance not provided 2015-01-15 no assertion criteria provided clinical testing

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