ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1517A>C (p.Gln506Pro) (rs397507548)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics, RCV000157683 SCV000927670 pathogenic not provided 2018-05-02 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000157683 SCV000281380 pathogenic not provided 2014-05-15 criteria provided, single submitter clinical testing
GeneDx RCV000157683 SCV000057455 pathogenic not provided 2018-11-26 criteria provided, single submitter clinical testing The Q506P missense variant has been previously reported in patients diagnosed with Noonan spectrum disorders including juvenile myelomonocytic leukemia (Conti et al., 2003; Kratz et al., 2005; Tartaglia et al., 2006; Loh et al. 2004). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Q506P 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 and in-silico analysis predicts this variant is probably damaging to the protein structure/ function. Functional studies of Q506P have shown that it affects the phosphatase domain (PTP) of the protein and interferes with its normal phosphatase activity (Qiu et al., 2014; Yu et. al, 2014). In addition, missense variants in nearby residues (R498W/L, R501K, S502A/T/L, G503R/A/E/V, M504V, T507K, Q510E/P/R/H) have been reported in the Human Gene Mutation Database in association with PTPN11-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the presence of the Q506P variant is consistent with the diagnosis of a Noonan spectrum disorder.
GeneReviews RCV000055887 SCV000086893 pathologic LEOPARD syndrome 1 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157683 SCV000207663 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Invitae RCV000033550 SCV000253878 pathogenic Rasopathy 2018-06-04 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 506 of the PTPN11 protein (p.Gln506Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome or Noonan syndrome with multiple lentigines, some of whom also had a myeloproliferative disorder (PMID: 18470943, 14961557, 15723289, 15928039, 20954246, 22528600). In at least one of these individuals, the variant likely arose de novo (PMID: 15928039). ClinVar contains an entry for this variant (Variation ID: 40563). Experimental studies have shown that this missense change alters the substrate specificity and structural configuration of the PTPN11 (Shp2) protein (PMID: 15987685, 24935154, 26742426). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154371 SCV000204036 pathogenic Noonan syndrome with multiple lentigines 2015-05-07 criteria provided, single submitter clinical testing The p.Gln506Pro variant has been reported in at least 6 individuals with the clinical features of LEOPARD syndrome (Conti 2003, Kratz 2005, Tartaglia 2006, Piard 2012, LMM unpublished data) and occurred de novo in 3 of these individuals (Conti 2003, Kratz 2005, Piard 2012). It was absent from large population studies. Additionally, in vitro functional studies provide some evidence that the p.Gln506Pro variant affects the protein function (Keilhack 2005, Yu 2014, Qiu 2014). In summary, the p.Gln506Pro variant in PTPN11 meets our criteria to be classified as pathogenic for LEOPARD syndrome in an autosomal dominant manner based upon absence from controls and de novo occurrences.

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