Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Genomic Medicine |
RCV001358687 | SCV007449263 | pathogenic | Noonan syndrome 1 | 2022-10-03 | criteria provided, single submitter | clinical testing | A different nucleotide change resulting in the same amino acid substitution has been reported as pathogenic (ACMG/AMP: PS1; PMIDs:15928039, 12634870, 16358218, 23321623, 25914815, 22190897, 20954246). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4_Supporting; PMIDs:15928039, 12634870, 16358218, 23321623, 25914815, 22190897, 20954246). This variant is located in a mutational hot spot and/or critical and well-established functional domain (ACMG/AMP: PM1; PMIDs:9491886, 16053901, 11992261). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2). This variant has been reported to occur de novo in an affected individual in the literature without parental identity confirmed (ACMG/AMP: PM6). 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). |
| Juno Genomics, |
RCV004795945 | SCV005418760 | pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | criteria provided, single submitter | clinical testing | Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. | |
| Genome Diagnostics Laboratory, |
RCV001813243 | SCV002060750 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2018-10-01 | criteria provided, single submitter | clinical testing | |
| Equipe Genetique des Anomalies du Developpement, |
RCV001358687 | SCV001554497 | pathogenic | Noonan syndrome 1 | criteria provided, single submitter | clinical testing | ||
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000587067 | SCV000698062 | pathogenic | Noonan syndrome 3 | 2016-01-25 | criteria provided, single submitter | clinical testing | Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and polar Asparagine (N) with a large size and basic Lysine (K). 4/4 in silico tools predict the variant to be disease causing. It is absent from the large and broad cohorts of the ExAC project while it was found in several NS patients either as a de novo or as a familiar mutation suggesting pathogenicity. Variants affecting the same amino acid, Asn58His and Asn58Asp, Asn58Tyr have been reported by our laboratory in the pathogenic spectrum suggesting the Asn58 residue to be a mutational hotspot and further supporting a casual outcome for the variant. Furthermore, clinical diagnostic centers classify variant as Pathogenic via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Pathogenic. |
| Labcorp Genetics |
RCV000556984 | SCV000659040 | pathogenic | RASopathy | 2025-12-03 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58Lys). This variant is not present in population databases (gnomAD no frequency). A different variant (c.174C>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 12634870, 15001945, 15956085, 16263833, 16358218, 19125092, 20954246, 21204800, 22190897, 23321623, 23624134, 23756559, 25914815). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 40488). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12634870, 15001945, 15956085, 16263833, 16358218, 19125092, 20954246, 21204800, 22190897, 23321623, 23624134, 23756559, 25914815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000037629 | SCV000061291 | pathogenic | Noonan syndrome | 2021-04-28 | criteria provided, single submitter | clinical testing | The p.Asn58Lys (c.174C>A) variant in PTPN11 has been reported in at least six individuals with Noonan syndrome and segregated with disease in one affected family member (Chan 2006, Miller 2017 PMID: 29212898, Sublett 2017 PMID: 28911804, D'Amico 2021 PMID: 33811550, LMM data). It has also been reported in one individual with multiple congenital anomalies (Retterer 2015 PMID:26633542). It was absent from large population studies, but has been reported in ClinVar (Variation ID 40488). Another variant resulting in the same amino acid change (c.174C>G) and two additional variants involving this codon (p.Asn58Asp and p.Asn58His) have been identified in individuals with Noonan syndrome and are classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP Criteria applied: PS1, PS4, PM5_Strong, PM2_Supporting. |
| Gene |
RCV000157677 | SCV000057361 | pathogenic | not provided | 2023-06-24 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Multiple pathogenic missense variants at this residue (p.N58D, p.N58Y, p.N58H) have been reported in association with Noonan spectrum disorders; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34184824, 26633542, 29212898, 28911804, 30050098, 29907801, 11992261, 9491886, 16053901, 29493581, 34782754) |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV000157677 | SCV000207648 | pathogenic | not provided | 2015-01-15 | no assertion criteria provided | clinical testing |