ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1471C>T (p.Pro491Ser) (rs397507539)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000157010 SCV000206737 pathogenic Noonan syndrome 2013-12-26 no assertion criteria provided clinical testing
Baylor Miraca Genetics Laboratories, RCV000033536 SCV000196652 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
GeneDx RCV000254684 SCV000057441 pathogenic not provided 2018-09-27 criteria provided, single submitter clinical testing The P491S pathogenic variant has been reported previously in the literature in patients with a clinical diagnosis of Noonan syndrome and the allelic disorder Noonan syndrome with multiple lentigines (Zenker et al., 2004; Bertola, et al., 2006; Tartaglia et al., 2006). In addition, other missense pathogenic variants altering this codon (P491T, P491L, P491H) have been reported in the literature (Ezquieta et al., 2012; Binder et al., 2005; Bertola et al., 2006). Functional studies show that this missense change results in increased phosphatase activity of the SHP-2 protein (Edwards et al., 2014). The P491S variant is not observed in large population cohorts (Lek et al., 2016). The P491S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret P491S as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000033536 SCV000920099 pathogenic Rasopathy 2018-08-13 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1471C>T (p.Pro491Ser) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain and Tyrosine specific protein phosphatases domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found in 1/246860 control chromosomes, a frequency of 4.1e-06. c.1471C>T has been reported in the literature in numerous individuals affected with Noonan Syndrome or related disorders, indicating the variant is very likely to be associated with disease. In addition, several variants causing a change at the same codon have been reported as associated with Noonan Syndrome (p.P491A, p.P491H, p.P491L, p.P491T), suggesting the proline is critical for proper gene function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000033536 SCV000549982 pathogenic Rasopathy 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 491 of the PTPN11 protein (p.Pro491Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs397507539, ExAC 0.001%). This variant has been observed to be de novo in an individual affected with Noonan syndrome (PMID: 22465605) and observed in unrelated individuals affected with this disease (PMID: 19077116, 16358218, 17020470). ClinVar contains an entry for this variant (Variation ID: 40550). 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"). Variants that disrupt the p.Pro491 amino acid residue in PTPN11 have been observed in affected individuals (PMID: 15985475, 19621452, 22465605). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000157010 SCV000061277 pathogenic Noonan syndrome 2018-12-19 criteria provided, single submitter clinical testing The p.Pro491Ser variant in PTPN11 has been identified in at least 10 individuals with clinical features of Noonan syndrome, including one individual in whom it occurred de novo (Bertola 2006, Tartaglia 2005, LMM data). This variant has also been identified as a somatic change occurring in an individual with acute lymph oblastic leukemia (Tartaglia 2004). It has been identified in 1/111708 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org/; dbSNP rs397507539). Additionally, at least 2 other pathogenic missens e variants (p.Pro491Thr; p.Pro491Leu; p.Pro491His) have been previously identifi ed at this codon of PTPN11 which may indicate that this residue is critical to t he function of the protein. In summary, this variant meets our criteria to be cl assified as pathogenic. ACMG/AMP codes applied: PS4, PM5_Strong, PM6

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