Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000810271 | SCV000950464 | likely pathogenic | Neurofibromatosis, type 1 | 2018-07-23 | criteria provided, single submitter | clinical testing | 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this nucleotide change can result in skipping of exon 22. Exon 22 is also known as exon 17 in the literature (PMID: 23913538). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with neurofibromatosis type 1 (PMID: 23913538, 29673180, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with lysine at codon 997 of the NF1 protein (p.Arg997Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 22 of the NF1 coding sequence, which is part of the consensus splice site for this exon. |
| Ambry Genetics | RCV002345833 | SCV001178976 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2019-05-07 | criteria provided, single submitter | clinical testing | The c.2990G>A pathogenic mutation (also known as p.R997K), located in coding exon 22 of the NF1 gene, results from a G to A substitution at nucleotide position 2990. The amino acid change results in arginine to lysine at codon 997, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 22, which makes it likely to have some effect on normal mRNA splicing. This alteration has been identified in a French NF1 cohort and is reported to result in exon skipping (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, a slight weakening in the native splice donor site efficiency and a weakening in the native splice donor site efficiency are predicted, respectively. Based on the available evidence, this variant is classified as a pathogenic mutation. . |
| Genome- |
RCV000810271 | SCV002561817 | likely pathogenic | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003467437 | SCV004190747 | likely pathogenic | Juvenile myelomonocytic leukemia | 2023-04-20 | criteria provided, single submitter | clinical testing |