Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000686766 | SCV000814299 | uncertain significance | Neurofibromatosis, type 1 | 2024-02-01 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 914 of the NF1 protein (p.Arg914Trp). This variant is present in population databases (rs765848298, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 566843). 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%. 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. |
| Ambry Genetics | RCV002440426 | SCV002748925 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2020-01-10 | criteria provided, single submitter | clinical testing | The p.R914W variant (also known as c.2740C>T), located in coding exon 21 of the NF1 gene, results from a C to T substitution at nucleotide position 2740. The arginine at codon 914 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported with a carrier frequency of 0.0000 in 7051 unselected breast cancer patients and 0.00009 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration has also been reported in two individuals with >5 cafe-au-lait macules. One of the individuals was reported to have abnormal development and pulmonic stenosis and was reported to carry a second variant in NF1 (deletion exons 2-3) (Koczkowska M et al. Am. J. Hum. Genet., 2018 01;102:69-87). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002507190 | SCV002815812 | uncertain significance | Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis | 2022-03-14 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV003442018 | SCV004170946 | uncertain significance | not provided | 2023-04-26 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with cafe au lait macules, and one individual also harbored a multi-exon deletion in NF1 (Koczkowska et al., 2018); This variant is associated with the following publications: (PMID: 29290338, 30287823, 25486365, 2121369) |