Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001065797 | SCV001230781 | likely pathogenic | Neurofibromatosis, type 1 | 2020-12-10 | 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. This variant disrupts the p.Met1440 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has been observed in individual(s) with clinical features of neurofibromatosis type I (PMID: 24789688). ClinVar contains an entry for this variant (Variation ID: 859637). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 1440 of the NF1 protein (p.Met1440Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. |
| Ambry Genetics | RCV002327345 | SCV002628172 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2020-09-10 | criteria provided, single submitter | clinical testing | The p.M1440V variant (also known as c.4318A>G), located in coding exon 32 of the NF1 gene, results from an A to G substitution at nucleotide position 4318. The methionine at codon 1440 is replaced by valine, an amino acid with highly similar properties. This alteration has been previously identified in an individual with a clinical diagnosis or clinical suspicion of neurofibromatosis type 1 (Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60). 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. |