ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.781C>T (p.Leu261Phe) (rs397507525)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000522926 SCV000616414 pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.781C>T (p.Leu261Phe) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 22465605; GeneDx, Cave lab internal data ClinVar SCV000057404.12). The p.Leu261Phe variant has also been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; SCV000061319.5, SCV000207687.1 PMID: 22465605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Moderate, PM2, PM1, PP2.
GeneDx RCV000157701 SCV000057404 pathogenic not provided 2016-10-26 criteria provided, single submitter clinical testing The L261F missense mutation in the PTPN11 gene has been reported in association with a PTPN11-related disorder (Ezquieta et al., 2012). This mutation as well as two other missense mutations that affect the same Leucine codon (L261R and L261H) have been observed previously at GeneDx in several unrelated individuals. Based on crystallography data, Leu261 is one of the critical residues in the PTP domain directly interacting with residues of the N-SH2 domain, which is required to block the active site of the SHP-2 tyrosine phosphatase protein (Hof et al. 1998). The variant is found in NOONAN panel(s).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037657 SCV000061319 pathogenic Noonan syndrome 2015-09-29 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV000522926 SCV000951642 pathogenic Rasopathy 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 261 of the PTPN11 protein (p.Leu261Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with Noonan syndrome (PMID: 22465605, 28074573). ClinVar contains an entry for this variant (Variation ID: 40520). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change results in enhanced ERK phosphorylation and catalytic activity in cell transfection studies (PMID: 28074573). This variant disrupts the p.Leu261 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 22253195, 23756559, 28074573), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157701 SCV000207687 likely pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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