ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.5C>T (p.Thr2Ile) (rs267606990)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033445 SCV000057350 pathogenic not provided 2021-05-05 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24803665, 16358218, 30050098, 29907801, 12960218, 20186801, 25337068, 25862627, 19449407, 32963807)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211847 SCV000061314 pathogenic Noonan syndrome 2016-02-10 criteria provided, single submitter clinical testing The p.Thr2Ile variant in PTPN11 has been identified in 6 individuals with clinic al features of Noonan syndrome (Sarkozy 2003, Tartaglia 2006, Thiel 2009, Louati 2014, LMM unpublished data), and was reported to have occurred de novo in 2 of these individuals (Thiel 2009, Louati 2014). Data from large population studies is insufficient to assess the frequency of this variant (dbSNP rs267606990). In summary, this variant meets our criteria to be classified as pathogenic for Noon an syndrome in an autosomal dominant manner based upon de novo occurrences.
Invitae RCV000694389 SCV000822833 pathogenic Rasopathy 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2 of the PTPN11 protein (p.Thr2Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in the literature in individuals affected with Noonan syndrome. In two of these individuals, this mutation was reported to be de novo (PMID: 12960218, 25337068, 19449407, 25862627). ClinVar contains an entry for this variant (Variation ID: 13349). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000694389 SCV000920094 pathogenic Rasopathy 2018-04-09 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.5C>T (p.Thr2Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 113882 control chromosomes (gnomAD and literature). c.5C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome/Leopard Syndrome (Sarkozy_2003, Thiel_2009, Tartaglia_2006, Louati_2014, vanTrier_2015, Pierpont_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000988912 SCV001138825 pathogenic Metachondromatosis 2019-05-28 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000014277 SCV001190299 pathogenic Noonan syndrome 1 2019-08-21 criteria provided, single submitter clinical testing
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong RCV000014277 SCV001364381 pathogenic Noonan syndrome 1 2020-06-02 criteria provided, single submitter research
OMIM RCV000014277 SCV000034526 pathogenic Noonan syndrome 1 2009-06-01 no assertion criteria provided literature only

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