ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.762ACA[2] (p.Gln257del)

dbSNP: rs397507524
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV002489463 SCV002778870 uncertain significance Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2021-11-15 criteria provided, single submitter clinical testing
Invitae RCV002549756 SCV002938004 uncertain significance RASopathy 2023-01-17 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this variant affects PTPN11 function (PMID: 32112654). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been observed in individual(s) with Noonan syndrome (PMID: 32112654). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant, c.768_770del, results in the deletion of 1 amino acid(s) of the PTPN11 protein (p.Gln257del), but otherwise preserves the integrity of the reading frame.
GeneDx RCV003229002 SCV003926424 likely pathogenic not provided 2022-12-13 criteria provided, single submitter clinical testing Published functional studies demonstrate that the Q257del variant enhances phosphatase activation/phosphorylation under the influence of the activating BTAM peptide in E.coli and EGF stimulation in HEK293 cells but not independently (Martinelli et al., 2020); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32112654, 9491886, 11992261, 16053901, 29493581)
PreventionGenetics, part of Exact Sciences RCV003953398 SCV004771700 uncertain significance PTPN11-related condition 2024-02-11 criteria provided, single submitter clinical testing The PTPN11 c.768_770delACA variant is predicted to result in an in-frame deletion (p.Gln257del). This variant was observed in an individual with a clinical diagnosis of Noonan syndrome, but was also observed in a parent and grandparent with no obvious or known features of Noonan syndrome (Martinelli et al. 2020. PubMed ID: 32112654). In the same study, the variant led to a mild activating effect using functional studies. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Human Genetics, University Hospital Magdeburg RCV000991102 SCV001132049 uncertain significance Noonan syndrome 1 2019-12-19 no assertion criteria provided clinical testing We found the variant in an affected girl. Her father also carries the variant, but is not affected. However, Noonan syndrome may be subtle in adults and clinical variation within families has been described. Two alleles were reported in gnomAD (AF 8.081e-6). Biochemical and functional studies show an activating effect, but not as strongly as for the Q257dup mutation.

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