Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000413557 | SCV000490914 | pathogenic | not provided | 2015-09-24 | criteria provided, single submitter | clinical testing | While the nucleotide substitution c.1390 G>A in the BRAF gene has not been reported previously, another nucleotide substitution at the same position, c.1390 G>C, has been published in association with Cardio-Facio-Cutaneous (CFC) Syndrome (Cave et al., 2008). Both nucleotide changes result in a non-conservative amino acid substitution of a highly conserved neutral, non-polar Glycine with a positively charged Arginine, designated G464R. The NHLBI ESP Exome Variant Server reports G464R 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. Additionally, in silico algorithms predict that G464R is not tolerated. Although this mutation has not been reported previously to our knowledge, its presence is consistent with a diagnosis of a Noonan spectrum disorder |
| Invitae | RCV000694211 | SCV000822645 | pathogenic | RASopathy | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 464 of the BRAF protein (p.Gly464Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with BRAF-related syndromes (PMID: 17704260; Invitae). ClinVar contains an entry for this variant (Variation ID: 372572). 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 BRAF protein function with a positive predictive value of 80%. This variant disrupts the p.Gly464 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18039235, 18413255, 19376813, 23907581). 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. |
| Database of Curated Mutations |
RCV000429423 | SCV000505052 | likely pathogenic | Melanoma | 2015-07-14 | no assertion criteria provided | literature only | |
| Service de Génétique Moléculaire, |
RCV000824916 | SCV000965948 | likely pathogenic | Cardio-facio-cutaneous syndrome | no assertion criteria provided | clinical testing | ||
| Laboratory of Virology, |
RCV002291625 | SCV002584881 | uncertain significance | Prostate cancer, hereditary, 1 | 2022-07-29 | no assertion criteria provided | clinical testing |