Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000159093 | SCV000209036 | uncertain significance | not provided | 2013-08-02 | criteria provided, single submitter | clinical testing | The V647I missense change has not been previously reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. V647I represents a conservative amino acid substitution as both Valine and Isoleucine are uncharged, non-polar amino acids. This change occurs at a moderately conserved residue. However, this variant is not located within any known functional domain and in silico models predict this change is benign. The NHLBI ESP Exome Variant Server reports V647I was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Although the majority of missense changes in RAF1 are pathogenic mutations, the potential for benign coding variants to exist in this gene must be considered. Based on information currently available, it is unclear whether V647I is a disease-causing mutation or a rare benign variant. The variant is found in NOONAN panel(s). |
| Labcorp Genetics |
RCV003539803 | SCV004344526 | uncertain significance | RASopathy | 2024-06-23 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 647 of the RAF1 protein (p.Val647Ile). This variant is present in population databases (rs730881008, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 181516). 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 not expected to disrupt RAF1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |