Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001061523 | SCV001226268 | uncertain significance | Neurofibromatosis, type 1 | 2023-09-14 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1412 of the NF1 protein (p.Pro1412Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with neurofibromatosis type-1 (PMID: 22807134). ClinVar contains an entry for this variant (Variation ID: 856126). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. Experimental studies have shown that this missense change does not substantially affect NF1 function (PMID: 22807134). 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. |
| Ambry Genetics | RCV002327334 | SCV002629677 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-06-24 | criteria provided, single submitter | clinical testing | The p.P1412R variant (also known as c.4235C>G), located in coding exon 31 of the NF1 gene, results from a C to G substitution at nucleotide position 4235. The proline at codon 1412 is replaced by arginine, an amino acid with dissimilar properties. In one study, this alteration was identified in a cohort of individuals with a clinical diagnosis of NF1. The alteration was found to be associated with mean fluorescence readings indicative of GTPase-activating protein-related domain (GRD) activity values comparable with those associated with wild-type, which the authors suggest is probably not deleterious to NF1-GRD function (Thomas L et al. Hum Mutat, 2012 Dec;33:1687-96). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |