Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000470292 | SCV000542198 | pathogenic | Neurofibromatosis, type 1 | 2024-07-24 | 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 848 of the NF1 protein (p.Gly848Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type 1 and neurofibromatosis (PMID: 17712740, 27482814, 29290338; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 404588). 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 NF1 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NF1 function (PMID: 26908603, 27482814). This variant disrupts the p.Gly848 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12552569, 23812910, 25211147, 29290338). 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. |
| UAB Medical Genomics Laboratory, |
RCV000470292 | SCV000999175 | pathogenic | Neurofibromatosis, type 1 | 2019-06-05 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002318997 | SCV001176749 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2020-10-21 | criteria provided, single submitter | clinical testing | The p.G848R pathogenic mutation (also known as c.2542G>C), located in coding exon 21 of the NF1 gene, results from a G to C substitution at nucleotide position 2542. The glycine at codon 848 is replaced by arginine, an amino acid with dissimilar properties. This mutation occurred de novo in one individual with a clinical or suspected diagnosis of neurofibromatosis type 1 (NF1) and co-segregated with NF1 in five unrelated families (Koczkowska M et al. Am. J. Hum. Genet., 2018 01;102:69-87). The alteration was also reported in a family with spinal neurofibromatosis (Pascual-Castroviejo I et al. Neuropediatrics, 2007 Apr;38:105-8). While mouse models harboring this mutation did not recapitulate the phenotype in humans, these mice had reduced neurofibromin expression (Li K et al. Dis Model Mech, 2016 07;9:759-67; Toonen JA et al. Hum. Mol. Genet., 2016 05;25:1703-13). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Genome- |
RCV000470292 | SCV002561790 | likely pathogenic | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing |