Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002311247 | SCV000581341 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2024-11-27 | criteria provided, single submitter | clinical testing | The p.D1623Y variant (also known as c.4867G>T), located in coding exon 36 of the NF1 gene, results from a G to T substitution at nucleotide position 4867. The aspartic acid at codon 1623 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in multiple patients with a clinical diagnosis or symptoms of NF1 (van Minkelen R et al. Clin. Genet., 2014 Apr;85:318-27; Ambry internal data). Different amino acid substitutions at the same position have also been identified in NF1 patients in other studies (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8; Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV002523992 | SCV003441802 | likely pathogenic | Neurofibromatosis, type 1 | 2022-04-15 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 429003). 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.Asp1623 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23913538; Invitae). 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. 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 aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1623 of the NF1 protein (p.Asp1623Tyr). |