ClinVar Miner

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

dbSNP: rs121918453
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033472 SCV000057377 pathogenic not provided 2024-04-11 criteria provided, single submitter clinical testing Identified in probands with ultrasound findings consistent with PTPN11-related RASopathy (PMID: 18759865, 26918529); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30355600, 15928039, 12717436, 26918529, 18759865)
Laboratory for Molecular Medicine, Mass General Brigham 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 RCV003103718 SCV000698069 pathogenic Noonan syndrome with multiple lentigines 2023-01-26 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.214G>C (p.Ala72Pro) results in a non-conservative amino acid change located in the N-terminal Src homology 2 (N-SH2) domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251056 control chromosomes. c.214G>C has been reported in the literature in individuals affected with Noonan Syndrome (example, PMID: 18759865, 26918529). At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 16358218). The most pronounced variant effect results in statistically significant higher phosphatase activities basally and after stimulation with BTAM peptide consistent with a gain of function mechanism of disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics RCV000033472 SCV000927439 pathogenic not provided 2017-10-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001852674 SCV002300216 likely pathogenic RASopathy 2022-07-01 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 72 of the PTPN11 protein (p.Ala72Pro). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 18759865). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala72 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12161469, 26918529). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40500).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.