Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000591453 | SCV000704787 | uncertain significance | not provided | 2016-12-20 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000765404 | SCV000896681 | uncertain significance | Niemann-Pick disease, type C1 | 2022-05-31 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000765404 | SCV003269799 | likely pathogenic | Niemann-Pick disease, type C1 | 2023-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1187 of the NPC1 protein (p.Ala1187Thr). This variant is present in population databases (rs762517273, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 499348). 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 with a positive predictive value of 95%. This variant disrupts the p.Ala1187 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26981555). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |