Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Center for Human Genetics, |
RCV000659989 | SCV000781910 | likely pathogenic | Neurofibromatosis, type 1 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000659989 | SCV000941482 | pathogenic | Neurofibromatosis, type 1 | 2023-07-29 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu499 amino acid residue in NF1. Other variant(s) that disrupt this residue have been observed in individuals with NF1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 547592). This missense change has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 26740943, 28529006). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 499 of the NF1 protein (p.Leu499Arg). |
Genome Diagnostics Laboratory, |
RCV000659989 | SCV001478949 | likely pathogenic | Neurofibromatosis, type 1 | 2020-10-26 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV000659989 | SCV002561669 | likely pathogenic | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002388166 | SCV002700145 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2021-09-27 | criteria provided, single submitter | clinical testing | The p.L499R variant (also known as c.1496T>G), located in coding exon 13 of the NF1 gene, results from a T to G substitution at nucleotide position 1496. The leucine at codon 499 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in an individual with NF1 or clinical suspicion of NF1 (Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25; Paulo P et al. J Mol Diagn, 2017 07;19:502-513). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |