ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.155C>T (p.Thr52Ile) (rs397507503)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000037621 SCV000616407 likely pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.155C>T (p.Thr52Ile) variant in PTPN11 has been identified in at least 5 independent occurrences in patients with a RASopathy (PS4_Moderate; PMID: 22465605, 25804457, GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381; SCV000057357.11; SCV000061283.5). This variant was absent from large population studies (PM2; ExAC, Computational prediction tools and conservation analysis suggest that the p.Thr52Ile variant may impact the protein (PP3). 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 likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM2, PP3, PP2.
GeneDx RCV000033452 SCV000057357 likely pathogenic not provided 2014-11-18 criteria provided, single submitter clinical testing The T51I substitution is a non-conservative amino acid substitution with a neutral, polar residue (Thr) being replaced by a neutral, non-polar residue (Ile). The position at which this substitution occurs is highly conserved in the PTPN11 protein and in related proteins. Other missense mutations in nearby codons (T42A, N58D, N58H, N58K, Y63C) have been reported in association with Noonan syndrome (Tartaglia et al., 2001; Musante et al., 2003; Tartaglia et al., 2006; Tartaglia et al., 2002). The NHLBI ESP Exome Variant Server reports that T52I was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The T52I missense change has been reported in the literature in a patient reported to have features consistent with a diagnosis of Noonan syndrome (Collazo et al., 2012). However, the patient's mother also harbored the T52I missense change and was indicated to have no features of Noonan syndrome (Collazo et al., 2012). Therefore, T52I is a strong candidate for a disease-causing mutation, but the possibility that it is a benign polymorphism cannot completely be excluded. The variant is found in NOONAN panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037621 SCV000061283 likely pathogenic Noonan syndrome 2016-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV000809051 SCV000949188 uncertain significance Rasopathy 2018-08-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 52 of the PTPN11 protein (p.Thr52Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in at least one individual with a suspected diagnosis of Noonan or Cardiofaciocutaneous (CFC) syndrome (PMID: 22465605, Collazo et al., 2012). This variant has also been reported in individuals affected with Noonan syndrome (PMID: 25804457). ClinVar contains an entry for this variant (Variation ID: 40484). 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"). 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.

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