Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000680803 | SCV000808247 | likely pathogenic | not provided | 2018-06-18 | criteria provided, single submitter | clinical testing | The T491R variant has been published previously in association with Noonan syndrome (Pandit et al., 2007). The variant is not observed in large population cohorts (Lek et al., 2016). T491R 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. Missense variants in the same residue (T491I) and in nearby residues (D486N/G, L489F) have been reported by the Human Gene Mutation Database and/or GeneDx in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Labcorp Genetics |
RCV001229313 | SCV001401755 | likely pathogenic | RASopathy | 2022-11-29 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr491 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603483, 22826437, 27753652). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RAF1 function (PMID: 22826437). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 13959). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17603483). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 491 of the RAF1 protein (p.Thr491Arg). |
| OMIM | RCV000014988 | SCV000035244 | pathogenic | Noonan syndrome 5 | 2007-08-01 | no assertion criteria provided | literature only |