Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV004994828 | SCV005459753 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2024-11-19 | criteria provided, single submitter | clinical testing | The c.3589G>C (p.A1197P) alteration is located in exon 27 (coding exon 27) of the NF1 gene. This alteration results from a G to C substitution at nucleotide position 3589, causing the alanine (A) at amino acid position 1197 to be replaced by a proline (P). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Two other alterations at the same codon, c.3590C>T (p.A1197V) and c.3589G>A (p.A1197T), have been detected in individuals with clinical features overlapping with neurofibromatosis type 1 (Martorana, 2023; Watanabe, 2023). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV005107618 | SCV005732623 | uncertain significance | Neurofibromatosis, type 1 | 2024-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1197 of the NF1 protein (p.Ala1197Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. This variant disrupts the p.Ala1197 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |