ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.228G>T (p.Glu76Asp)

dbSNP: rs397507514
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254683 SCV000057383 pathogenic not provided 2022-02-25 criteria provided, single submitter clinical testing Reported previously in association with Noonan syndrome (Tartaglia et al., 2006; Musante et al., 2003); Published functional studies demonstrate a damaging effect; p.(E76D) results in abnormally increased activity levels of the PTPN11 protein (Tartaglia et al., 2006; Bocchinfuso et al., 2007); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12634870, 20308328, 17177198, 29907801, 30029678, 16830086, 30050098, 32676024, 16358218, 24077912, 27535533, 11992261, 9491886, 16053901, 29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037639 SCV000061301 pathogenic Noonan syndrome 2022-04-01 criteria provided, single submitter clinical testing The p.Glu76Asp (c.228G>T) variant in PTPN11 has been reported in at least 10 individuals with clinical features of Noonan syndrome (Musante 2003 PMID: 12634870, Tartaglia 2006 PMID: 16358218, Power 2006 PMID: 16830086, Digilio 2011 PMID: 22190897, Zhu 2018 PMID: 30029678, Leach 2019 PMID: 29907801, LMM data) and has also been reported by other clinical laboratories in ClinVar (Variation ID 40502). It was absent from large population studies. Notably, a different nucleotide substitution at the same position (c.228G>C) resulting in the same amino acid change has been reported in >10 individuals with clinical features of Noonan syndrome (Tartaglia 2001 PMID: 11704759, Tartaglia 2006 PMID: 16358218, Edouard 2010 PMID: 20308328, LMM data). In addition, there are 4 other pathogenic amino acid substitutions at this position (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly); all these variants were also absent in large population studies. In vitro functional studies support an impact on protein function (Keilhack 2005 PMID: 15987685, Bocchinfuso 2007 PMID: 17177198, Edouard 2010 PMID: 20308328). Additionally, this variant lies in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (Gelb 2018 PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5_Strong, PS3_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000033478 SCV000698072 pathogenic RASopathy 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.228G>T (p.Glu76Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 122184 control chromosomes (ACMG PM2). This variant is found in the N-SH2 domain (IPR000980), a regulatory module of intracellular signaling cascades through its interaction with high affinity to phosphotyrosine-containing target peptides (ACMG PM1). This is a hotspot, with multiple missense variants in the same residue being known likely pathogenic variants (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly). In addition, multiple functional studies (Tartaglia_AJHG_2006, Edouard_MCB_2010, Keilhack_JBC_2005) showed that this variant increased basal and stimulated phosphatase activity by as much as 3-fold, determining a gain-of-function phenotype (ACMG PS3). This variant, and another variant c.228G>C that leads to the same amino acid change (E76D) have been reported in several patients with a clinical diagnosis of Noonan syndrome (ACMG PS1). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic (ACMG PP5). Lastly, these evidences support the classification of this variant as "Pathogenic" based upon ACMG guidelines (PS1, PS3, PM1, PM2, PP5). Taken together, this variant is classified as Pathogenic.
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000037639 SCV000840427 pathogenic Noonan syndrome 2018-04-13 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000762884 SCV000893272 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000254683 SCV000928217 pathogenic not provided 2019-02-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000033478 SCV001394745 pathogenic RASopathy 2023-10-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 76 of the PTPN11 protein (p.Glu76Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 12634870, 16830086, 18678287, 22190897). ClinVar contains an entry for this variant (Variation ID: 40502). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15834506, 16358218, 17177198). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813246 SCV002060932 pathogenic Noonan syndrome and Noonan-related syndrome 2020-08-05 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000254683 SCV005197297 pathogenic not provided 2022-07-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV000033478 SCV000196662 pathogenic RASopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand RCV003150934 SCV003840156 pathogenic Noonan syndrome 1 no assertion criteria provided research
PreventionGenetics, part of Exact Sciences RCV004734537 SCV005362203 pathogenic PTPN11-related disorder 2024-08-17 no assertion criteria provided clinical testing The PTPN11 c.228G>T variant is predicted to result in the amino acid substitution p.Glu76Asp. This variant has been reported in many individuals with Noonan syndrome (Tartaglia et al. 2006. PubMed ID: 16358218; Table S3, Leach et al. 2019. PubMed ID: 29907801; Table S4, Zhu et al. 2018. PubMed ID: 30029678). Functional studies support this variants pathogenicity (Edouard et al. 2010. PubMed ID: 20308328). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/40502/). An alternate nucleotide substitution resulting in the same missense variant (c.228G>C (p.Glu76Asp)) has been reported as pathogenic (ClinVar ID: 40503). Alternate amino acid substitutions affecting this amino acid (p.Glu76Gln, p.Glu76Ala, p.Glu76Gly, p.Glu76Val) have been interpreted as pathogenic in ClinVar (ClinVar IDs: 181496, 13339, 13338, 13337). This variant is interpreted as pathogenic.

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