ClinVar Miner

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

dbSNP: rs267606990
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033445 SCV000057350 pathogenic not provided 2022-06-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 16358218, 30050098, 29907801, 12960218, 20186801, 25862627, 19449407, 32963807, 25337068)
Laboratory for Molecular Medicine, Mass General Brigham 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in 6 individuals with clinic al features of Noonan syndrome (Sarkozy 2003, Tartaglia 2006, Thiel 2009, Louati 2014, LMM unpublished data), and was reported to have occurred de novo in 2 of these individuals (Thiel 2009, Louati 2014).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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000694389 SCV000822833 pathogenic RASopathy 2024-01-12 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2 of the PTPN11 protein (p.Thr2Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 12960218, 19449407, 25337068, 25862627). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13349). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. 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
Genetic Services Laboratory, University of Chicago RCV000033445 SCV002067495 pathogenic not provided 2020-06-24 criteria provided, single submitter clinical testing DNA sequence analysis of the PTPN11 gene demonstrated a sequence change, c.5C>T, in exon 1 that results in an amino acid change, p.Thr2Ile. This sequence change has not been described in population databases gnomAD, ExAC). The p.Thr2Ile change has been reported in several individuals with Noonan syndrome. In two of these individuals, this sequence change was reported to be de novo (PMIDs: 12960218, 19449407, 25337068, 25862627). The p.Thr2Ile change affects a moderately conserved amino acid residue located in a domain of the PTPN11 protein that is known to be functional. The p.Thr2Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Pathogenic missense variants in the PTPN11 gene are predominantly missense in nature. This sequence change likely causes a disease phenotype, however functional studies have not been performed to prove this conclusively.
AiLife Diagnostics, AiLife Diagnostics RCV000033445 SCV002501712 likely pathogenic not provided 2022-01-01 criteria provided, single submitter clinical testing
3billion RCV000014277 SCV002521238 pathogenic Noonan syndrome 1 2022-05-22 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.21; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013349). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 19449407,25337068,25862627). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000014277 SCV002557837 pathogenic Noonan syndrome 1 2022-06-24 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene, and have been associated with metachondromatosis (MIM#156250) and Noonan syndrome 1 (MIM#163950), respectively (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in individuals with Noonan syndrome. One individual was also reported with a high grade glioma (ClinVar, PMID: 30693642). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV000014277 SCV002559207 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000014277 SCV002761725 pathogenic Noonan syndrome 1 2022-03-22 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496356 SCV002810790 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2021-10-02 criteria provided, single submitter clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles RCV003156060 SCV003845261 pathogenic See cases 2022-12-21 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000014277 SCV004698049 pathogenic Noonan syndrome 1 2024-02-13 criteria provided, single submitter clinical testing Criteria applied: PS2_VSTR,PS4,PM2_SUP,PP2
Juno Genomics, Hangzhou Juno Genomics, Inc RCV004795408 SCV005418552 pathogenic LEOPARD syndrome 1 criteria provided, single submitter clinical testing PM2_Supporting+PS4+PP4+PS2
OMIM RCV000014277 SCV000034526 pathogenic Noonan syndrome 1 2009-06-01 no assertion criteria provided literature only
GenomeConnect - Brain Gene Registry RCV000014277 SCV003931156 not provided Noonan syndrome 1 no assertion provided phenotyping only Variant classified as Pathogenic and reported on 12-12-2018 by UCLA Laboratory Genetics and Genomics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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