Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001228353 | SCV001400748 | uncertain significance | Neurofibromatosis, type 1 | 2022-05-29 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1165 of the NF1 protein (p.Ile1165Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1, breast cancer, and malignant peripheral nerve sheath tumor (PMID: 30530636). ClinVar contains an entry for this variant (Variation ID: 955671). This variant disrupts the p.Ile1165 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). |
| Ambry Genetics | RCV002451535 | SCV002612900 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2021-11-27 | criteria provided, single submitter | clinical testing | The p.I1165T variant (also known as c.3494T>C), located in coding exon 26 of the NF1 gene, results from a T to C substitution at nucleotide position 3494. The isoleucine at codon 1165 is replaced by threonine, an amino acid with similar properties. This alteration was identified in an individual in a cohort of individuals with a clinical diagnosis or clinical suspicion of neurofibromatosis type 1 (Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |