Total submissions: 22
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Genomic Medicine |
RCV000014277 | SCV007449273 | pathogenic | Noonan syndrome 1 | 2025-11-17 | criteria provided, single submitter | clinical testing | This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4; PMIDs:12960218, 16358218, 20186801, 25337068, 25862627, 29907801, 30693642, 32963807, 19449407). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2_Supporting). This variant has been reported to occur de novo in an affected individual in the literature without parental identity confirmed (ACMG/AMP: PM6_Strong; PMIDs:19449407, 32963807). This variant occurs in a gene with a low rate of benign missense variation, in which missense alterations are a common mechanism of disease (ACMG/AMP: PP2). |
| Revvity Omics, |
RCV000033445 | SCV006321541 | pathogenic | not provided | 2025-05-29 | criteria provided, single submitter | clinical testing | |
| Clinical Genomics Laboratory, |
RCV000014277 | SCV005685330 | pathogenic | Noonan syndrome 1 | 2024-06-10 | criteria provided, single submitter | clinical testing | The PTPN11 c.5C>T (p.Thr2Ile) variant has been reported in several individuals affected with Noonan syndrome and the variant reportedly occurred de novo in at least two reported individuals (El-Ayadi M et al., PMID: 30693642. Fung JLF et al., PMID: 32963807; Louati R et al., PMID: 25337068; Sarkozy A et al., PMID: 12960218; Thiel C et al., PMID: 19449407; van Trier DC et al., PMID: 25862627). This variant has been reported in the ClinVar database as a germline pathogenic variant by several submitters and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. |
| Juno Genomics, |
RCV004795408 | SCV005418552 | likely pathogenic | LEOPARD syndrome 1 | criteria provided, single submitter | clinical testing | The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. | |
| Institute of Human Genetics, |
RCV000014277 | SCV004698049 | pathogenic | Noonan syndrome 1 | 2024-02-13 | criteria provided, single submitter | clinical testing | Criteria applied: PS2_VSTR,PS4,PM2_SUP,PP2 |
| Center for Personalized Medicine, |
RCV003156060 | SCV003845261 | pathogenic | See cases | 2022-12-21 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002496356 | SCV002810790 | pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2021-10-02 | criteria provided, single submitter | clinical testing | |
| Genetics and Molecular Pathology, |
RCV000014277 | SCV002761725 | pathogenic | Noonan syndrome 1 | 2022-03-22 | criteria provided, single submitter | clinical testing | |
| Centre de Biologie Pathologie Génétique, |
RCV000014277 | SCV002559207 | pathogenic | Noonan syndrome 1 | criteria provided, single submitter | clinical testing | ||
| Victorian Clinical Genetics Services, |
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 |
| 3billion | RCV000014277 | SCV002521238 | pathogenic | Noonan syndrome 1 | 2023-07-17 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013349 /PMID: 12960218 /3billion dataset). 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. |
| Ai |
RCV000033445 | SCV002501712 | likely pathogenic | not provided | 2022-01-01 | criteria provided, single submitter | clinical testing | |
| Genetic Services Laboratory, |
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. |
| Department of Paediatrics and Adolescent Medicine, |
RCV000014277 | SCV001364381 | pathogenic | Noonan syndrome 1 | 2020-06-02 | criteria provided, single submitter | research | |
| Equipe Genetique des Anomalies du Developpement, |
RCV000014277 | SCV001190299 | pathogenic | Noonan syndrome 1 | 2019-08-21 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000988912 | SCV001138825 | pathogenic | Metachondromatosis | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
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. |
| Labcorp Genetics |
RCV000694389 | SCV000822833 | pathogenic | RASopathy | 2026-01-13 | 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). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) 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. |
| Laboratory for Molecular 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. |
| Gene |
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) |
| Genome |
RCV000014277 | SCV003931156 | not provided | Noonan syndrome 1 | no classification 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/. | |
| OMIM | RCV000014277 | SCV000034526 | pathogenic | Noonan syndrome 1 | 2009-06-01 | no assertion criteria provided | literature only |