Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002315842 | SCV000674095 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2016-10-18 | criteria provided, single submitter | clinical testing | The p.L578P variant (also known as c.1733T>C), located in coding exon 16 of the NF1 gene, results from a T to C substitution at nucleotide position 1733. The leucine at codon 578 is replaced by proline, an amino acid with similar properties. This alteration has been reported in two individuals meeting diagnostic criteria for neurofibromatosis type 1 (Jeong SY et al. J. Korean Med. Sci., 2006 Feb;21:107-12; Bausch B et al. J. Clin. Endocrinol. Metab., 2007 Jul;92:2784-92). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001064262 | SCV001229151 | pathogenic | Neurofibromatosis, type 1 | 2023-10-20 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 578 of the NF1 protein (p.Leu578Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 16479075, 17426081). ClinVar contains an entry for this variant (Variation ID: 485956). 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. This variant disrupts the p.Leu578 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12746402, 23668869, 25211147). 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. |
| Medical Genetics, |
RCV001064262 | SCV002567783 | likely pathogenic | Neurofibromatosis, type 1 | 2022-08-17 | criteria provided, single submitter | clinical testing | |
| MGZ Medical Genetics Center | RCV001064262 | SCV002579681 | likely pathogenic | Neurofibromatosis, type 1 | 2021-11-11 | criteria provided, single submitter | clinical testing |