Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165811 | SCV000216558 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-09-23 | criteria provided, single submitter | clinical testing | ​<span style="background-color: initial;">The<strong style="background-color: initial;">p.R1000L<span style="background-color: initial;"> variant (also known as c.2999G>T), located in coding exon 23 of the<em style="background-color: initial;">NF1<span style="background-color: initial;"> gene, results from a G to T substitution at nucleotide position 2999. The arginine at codon 1000 is replaced by leucine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 11000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and deleterious by PolyPhen and SIFT<em style="background-color: initial;">in silico<span style="background-color: initial;"> analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.R1000L remains unclear. |
| Invitae | RCV000706070 | SCV000835101 | uncertain significance | Neurofibromatosis, type 1 | 2023-07-31 | 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. This variant disrupts the p.Arg1000 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25074460, 27838393, 34080803). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 186250). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1000 of the NF1 protein (p.Arg1000Leu). |
| Genome- |
RCV000706070 | SCV002560251 | uncertain significance | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002498819 | SCV002783329 | uncertain significance | Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis | 2022-02-09 | criteria provided, single submitter | clinical testing |