Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000494366 | SCV000581732 | uncertain significance | not provided | 2017-04-14 | criteria provided, single submitter | clinical testing | The L2302P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L2302P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L2302P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense variants associated with NF1 have been reported in nearby residues in the Human Gene Mutation Database (Stenson et al., 2014). In summary, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant. |
| Center for Human Genetics, |
RCV000660111 | SCV000782095 | uncertain significance | Neurofibromatosis, type 1 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000660111 | SCV001394822 | uncertain significance | Neurofibromatosis, type 1 | 2023-03-18 | criteria provided, single submitter | clinical testing | 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. 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: 429223). This missense change has been observed in individual(s) with clinical features of NF1-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2302 of the NF1 protein (p.Leu2302Pro). |
| Genome- |
RCV000660111 | SCV002561020 | uncertain significance | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002367669 | SCV002661445 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-04-27 | criteria provided, single submitter | clinical testing | The p.L2302P variant (also known as c.6905T>C), located in coding exon 46 of the NF1 gene, results from a T to C substitution at nucleotide position 6905. The leucine at codon 2302 is replaced by proline, an amino acid with similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with NF1-related disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |