Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001062713 | SCV001227529 | pathogenic | Neurofibromatosis, type 1 | 2024-03-16 | 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 90 of the NF1 protein (p.Leu90Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type I (PMID: 17426081, 30046999; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 857101). 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%. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002429699 | SCV002742729 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-01-27 | criteria provided, single submitter | clinical testing | The p.L90P variant (also known as c.269T>C), located in coding exon 3 of the NF1 gene, results from a T to C substitution at nucleotide position 269. The leucine at codon 90 is replaced by proline, an amino acid with similar properties. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in multiple individuals meeting clinical diagnostic criteria for neurofibromatosis type 1 (NF1) (Bausch B et al. J Clin Endocrinol Metab, 2007 Jul;92:2784-92; Xiao H et al. J Mol Neurosci, 2018 Aug;65:557-563). 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. |
| NHS Central & South Genomic Laboratory Hub | RCV001062713 | SCV005393951 | pathogenic | Neurofibromatosis, type 1 | 2024-11-11 | criteria provided, single submitter | clinical testing |