ClinVar Miner

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

gnomAD frequency: 0.00007  dbSNP: rs397516797
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Total submissions: 11
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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,Mass General Brigham 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 2021-12-04 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 560 of the PTPN11 protein (p.Leu560Phe). This variant is present in population databases (rs397516797, gnomAD 0.01%). This missense change has been observed in individual(s) with Noonan syndrome and congenital hypertrophic cardiomyopathy (PMID: 12960218). ClinVar contains an entry for this variant (Variation ID: 44599). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PTPN11 protein function. Experimental studies have shown that this missense change does not substantially affect PTPN11 function (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
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813327 SCV002060838 uncertain significance Noonan syndrome and Noonan-related syndrome 2016-12-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037623 SCV002511653 uncertain significance not specified 2022-04-05 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1678C>T (p.Leu560Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251088 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PTPN11 causing Noonan Syndrome (4e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.1678C>T has been reported in the literature in at-least one individual affected with Hypertrophic Cardiomyopathy (example, Sarkozy_2003). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on biochemical function (example, Keilhack_2005). Six clinical diagnostic laboratories and an expert panel (ClinGen RASopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (Likely benign, n=3 and VUS, n=4). An alternate molecular basis of disease has been summarized by the expert panel but the exact co-occurrence is not specified. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157702 SCV000207690 uncertain significance not provided 2015-01-15 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000157702 SCV001800456 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000157702 SCV001952659 likely benign not provided no assertion criteria provided clinical testing

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