Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000756436 | SCV000884254 | uncertain significance | not provided | 2018-04-02 | criteria provided, single submitter | clinical testing | The NF1 c.556G>T; p.Asp186Tyr variant is reported in the literature in an individual with classical NF1 and spinal tumors (Upadhyaya 2009). In addition, a different alteration at this codon (p.Asp186Val) is also reported in an individual with NF1 (Zatkova 2004). The p.Asp186Tyr variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartate at codon 186 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant is deleterious. However, due to limited information, the clinical significance of p.Asp186Tyr is uncertain at this time. REFERENCES Upadhyaya M et al. The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics. 2009 Jul;10(3):251-63. Zatkova A et al. Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1. Hum Mutat. 2004 Dec;24(6):491-501. |
| Invitae | RCV001214491 | SCV001386174 | likely pathogenic | Neurofibromatosis, type 1 | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 186 of the NF1 protein (p.Asp186Tyr). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 19221814; Invitae). ClinVar contains an entry for this variant (Variation ID: 618253). 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%. Studies have shown that this missense change results in activation of a cryptic splice site and/or skipping of exon 5 and introduces a premature termination codon (PMID: 34782607). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Genome- |
RCV001214491 | SCV002561484 | uncertain significance | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002507322 | SCV002816831 | uncertain significance | Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis | 2021-10-11 | criteria provided, single submitter | clinical testing |