ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.124A>G (p.Thr42Ala) (rs397507501)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157675 SCV000057355 pathogenic not provided 2021-09-16 criteria provided, single submitter clinical testing Published functional studies demonstrate a significant increase in phosphopeptide binding affinity without greatly altering binding specificity or secondary structure of the domain (Keilhack et al., 2005; Muller et al., 2013); Not observed at significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29493581, 33258288, 32668055, 31936901, 32164556, 31560489, 31219622, 29907801, 30050098, 30417923, 29988639, 22781091, 28483241, 11992261, 17661820, 21590266, 16358218, 24803665, 25425531, 15987685, 23584145, 18372317)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000157002 SCV000061270 pathogenic Noonan syndrome 2013-01-25 criteria provided, single submitter clinical testing The Thr42Ala variant in PTPN11 has been reported in 10 individuals in the litera ture (Tartaglia 2002, Sarkozy 2003, Zenker 2004, Lee 2007, Shaw 2007, Martinelli 2008, Digilio 2012) and one individual in our laboratory with clinical features of Noonan syndrome. This variant was reported to have occurred de novo in at le ast one of these individuals (Digilio 2012). In summary, this variant meets our criteria to be classified as pathogenic (
Blueprint Genetics RCV000157002 SCV000264157 pathogenic Noonan syndrome 2015-06-19 criteria provided, single submitter clinical testing
Invitae RCV000227194 SCV000287692 pathogenic Rasopathy 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 42 of the PTPN11 protein (p.Thr42Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Noonan syndrome (PMID: 16358218, 15001945, 22781091, 21590266, 17661820). ClinVar contains an entry for this variant (Variation ID: 40482). This variant has been reported to affect PTPN11 protein function (PMID: 15987685, 18372317, 23584145). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000227194 SCV001361724 pathogenic Rasopathy 2019-03-25 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.124A>G (p.Thr42Ala) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246614 control chromosomes (gnomAD). c.124A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome, including de novo cases (Tartaglia_2002, Sarkozy_2003, Zenker_2004, Lee_2007, VanTrier_2015, Tamura_2018, Ezquieta_2012). These data indicate that the variant is very likely to be associated with disease. This variant exhibits increased affinity for mono-Tyr(P) peptide and phosphopeptide (Keilhack_2005 and Martinelli_2008), which is believed to be one of the mechanisms of SHP2's functional dysregulation. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV001330777 SCV001522569 pathogenic Noonan syndrome 1 2020-06-03 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000157002 SCV000206726 pathogenic Noonan syndrome 2012-01-27 no assertion criteria provided clinical testing
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157675 SCV000207646 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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