Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002050898 | SCV002116893 | likely pathogenic | Niemann-Pick disease, type C1 | 2021-10-10 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with NPC1-related conditions. 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.Ser734 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12955717, 20718790, 23433426, 26666848). 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. 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 NPC1 protein function. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with glycine at codon 734 of the NPC1 protein (p.Ser734Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. |