ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1472C>A (p.Pro491His) (rs397507540)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033537 SCV000057442 pathogenic not provided 2019-05-16 criteria provided, single submitter clinical testing The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17020470, 24803665, 17546245, 30417923, 31560489)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037617 SCV000061279 pathogenic Noonan syndrome 2015-09-29 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Blueprint Genetics RCV000033537 SCV000927247 pathogenic not provided 2017-05-04 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000033537 SCV001446672 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Invitae RCV001378165 SCV001575676 likely pathogenic Rasopathy 2020-02-27 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 491 of the PTPN11 protein (p.Pro491His). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Noonan syndrome (PMID: 17546245, 21590266, 17020470). ClinVar contains an entry for this variant (Variation ID: 40551). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Pro491 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15985475, 22781091, 23624134, 20186801, 18470943). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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