Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000497187 | SCV000961388 | uncertain significance | Neurofibromatosis, type 1 | 2020-11-10 | criteria provided, single submitter | clinical testing | 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 an individual affected with neurofibromatosis type-1 (PMID: 26740943). ClinVar contains an entry for this variant (Variation ID: 431666). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 2028 of the NF1 protein (p.Lys2028Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 40 of the NF1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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 | RCV002356814 | SCV002659913 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-05-27 | criteria provided, single submitter | clinical testing | The c.6084G>C variant (also known as p.K2028N), located in coding exon 40 of the NF1 gene, results from a G to C substitution at nucleotide position 6084. The amino acid change results in lysine to asparagine at codon 2028, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 40, which makes it likely to have some effect on normal mRNA splicing. This alteration was detected in an individual with neurofibromatosis type 1 (NF1) or clinical suspicion of NF1 (Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV004760534 | SCV005369033 | uncertain significance | not provided | 2024-04-03 | criteria provided, single submitter | clinical testing | Observed in an individual with spinal neurofibromatosis not fulfilling clinical criteria for diagnosis (PMID: 36612057, 37751797); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26740943, 37751797, 36612057) |
| Medical Genetics, |
RCV000497187 | SCV000588811 | likely pathogenic | Neurofibromatosis, type 1 | 2017-02-02 | no assertion criteria provided | clinical testing |