ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs141140214
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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, http://exac.broadinstitute.org; d bSNP rs141140214).
GeneDx RCV000680301 SCV000209001 likely benign not provided 2020-06-17 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware 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
Labcorp Genetics (formerly Invitae), Labcorp RCV000690056 SCV000817733 uncertain significance RASopathy 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 561 of the PTPN11 protein (p.Pro561Leu). This variant is present in population databases (rs141140214, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 2022-10-16 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.
Ambry Genetics RCV002399540 SCV002712855 likely benign Cardiovascular phenotype 2021-10-04 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen RCV000680301 SCV004131975 likely benign not provided 2023-07-01 criteria provided, single submitter clinical testing PTPN11: PP2, BS2

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