Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000037920 | SCV000061583 | likely pathogenic | Noonan syndrome | 2012-02-02 | criteria provided, single submitter | clinical testing | The Thr470Arg variant has not been reported in the literature nor previously ide ntified in over 1,400 Caucasian individuals tested by our laboratory. Since this variant was not identified in either of the parents of this individual, the var iant has likely occurred de novo, assuming that non-medical explanations includi ng alternate paternity or undisclosed adoption have been ruled out. Furthermore, this variant occurs within the functionally important G-loop of the BRAF tyrosi ne kinase domain and computational analyses (biochemical amino acid properties, conservation, PolyPhen2, SIFT, AlignGVGD) suggest that the Thr470Arg variant may impact the protein. However, this information is not predictive enough to deter mine pathogenicity. In summary, this variant is likely to be pathogenic, based o n the likely de novo occurrence of this variant in this individual. |
| Gene |
RCV000681421 | SCV000808884 | likely pathogenic | not provided | 2018-07-20 | criteria provided, single submitter | clinical testing | The T470R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant has been observed apparently de novo in another affected individual by another clinical laboratory in ClinVar (SCV000061583.5; Landrum et al., 2016). The T470R variant is not observed in large population cohorts (Lek et al., 2016). The T470R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Pathogenic missense variants in nearby residues (S467A, F468S, G469E) have been reported in the Human Gene Mutation Database in association with Cardio-Facio-Cutaneous syndrome (CFC) (Stenson et al., 2014). In summary, based on the currently available information, this variant is likely pathogenic. |
| Service de Génétique Moléculaire, |
RCV000037920 | SCV001438446 | uncertain significance | Noonan syndrome | no assertion criteria provided | clinical testing |