Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000159045 | SCV000208987 | pathogenic | not provided | 2014-08-04 | criteria provided, single submitter | clinical testing | he E76Q missense mutation has not be reported as a benign polymorphism or as a disease-causing mutation, to our knowledge. The E76Q missense change is a non-conservative amino acid substitution with a negatively charged residue (Glu) being replaced by a neutral residue (Gln). It lies in the N-SH2 domain of the gene, which is a hot spot for Noonan syndrome mutations. Several other missense mutations at this codon (E76A, E76K and E76V) have been reported as somatic mutations in association with juvenile myelomonocytic leukemia (JMML) and other hematologic malignancies (Mori et al., 2004 and Tartaglia et al., 2006). However, another missense mutation at this codon (E76D) has been reported previously as a germline mutation in association with Noonan syndrome (Tartaglia et al., 2001 and Tartaglia et al., 2006). The variant is found in NOONAN panel(s). |
| Genome Diagnostics Laboratory, |
RCV001813410 | SCV002060930 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2017-05-15 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002281971 | SCV002570731 | pathogenic | RASopathy | 2022-07-25 | criteria provided, single submitter | clinical testing | Variant summary: PTPN11 c.226G>C (p.Glu76Gln) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Other variants at the same codon, p.Glu76Ala, p.Glu76Asp, p.Glu76Gly and p.Glu76Val have been reported in association with Noonan syndrome supporting a mutational hotspot and a critical residue required for protein function. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251068 control chromosomes. c.226G>C has been reported in the literature as a de-novo germline variant in at-least one fetus prenatally affected with Noonan Syndrome (example, Malniece_2020). At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant resulted in increased phosphatase activity as compared with wild type, therefore, this alteration is predicted to be activating (LaRochelle_2016). One clinical diagnostic laboratory has 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. |
| MGZ Medical Genetics Center | RCV002288669 | SCV002581080 | pathogenic | Noonan syndrome 1 | 2022-07-07 | criteria provided, single submitter | clinical testing | |
| Genomic Medicine Center of Excellence, |
RCV002288669 | SCV004806648 | likely pathogenic | Noonan syndrome 1 | 2024-03-26 | criteria provided, single submitter | clinical testing |