ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1682C>T (p.Pro561Leu) (rs141140214)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154538 SCV000204210 likely benign not specified 2015-08-14 criteria provided, single submitter clinical testing p.Pro561Leu in exon 14 of PTPN11: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 3 mammals have a leucine (Leu) at this position despite high nearby amin o acid conservation. It has also been identified in 5/66606 of European chromoso mes by the Exome Aggregation Consortium (ExAC,; d bSNP rs141140214).
GeneDx RCV000680301 SCV000209001 likely benign not provided 2018-02-01 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.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000154538 SCV000265846 uncertain significance not specified 2015-10-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515184 SCV000611507 uncertain significance Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-23 criteria provided, single submitter clinical testing
Invitae RCV000690056 SCV000817733 uncertain significance Rasopathy 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 561 of the PTPN11 protein (p.Pro561Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs141140214, ExAC 0.008%). This variant has not been reported in the literature in individuals with PTPN11-related disease. ClinVar contains an entry for this variant (Variation ID: 177887). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154538 SCV001467848 likely benign not specified 2020-12-21 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1682C>T (p.Pro561Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 395798 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database (i.e. in the gnomAD v2.1 and gnomAD v3.1 (non-v2) dataset), including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1682C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. 2 calling it likely benign, while 3 classifying it as a VUS). Based on the evidence outlined above, the variant was classified as likely benign.

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