Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002357209 | SCV002658742 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-05-25 | criteria provided, single submitter | clinical testing | The p.S1997R variant (also known as c.5989A>C), located in coding exon 40 of the NF1 gene, results from an A to C substitution at nucleotide position 5989. The serine at codon 1997 is replaced by arginine, an amino acid with dissimilar properties. 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. |
| Labcorp Genetics |
RCV001353286 | SCV005813106 | pathogenic | Neurofibromatosis, type 1 | 2024-04-06 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1997 of the NF1 protein (p.Ser1997Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type I (PMID: 30308447, 32575496, 34694046). In at least one individual the variant was observed to be de novo. This variant is also known as p.Ser2018Arg. ClinVar contains an entry for this variant (Variation ID: 1048699). 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%. Experimental studies have shown that this missense change affects NF1 function (PMID: 34694046). This variant disrupts the p.Ser1997 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. For these reasons, this variant has been classified as Pathogenic. |
| Laboratory of Medical Genetics, |
RCV001353286 | SCV001548412 | likely pathogenic | Neurofibromatosis, type 1 | 2019-01-01 | no assertion criteria provided | clinical testing |