Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003064507 | SCV003442434 | likely pathogenic | Niemann-Pick disease, type C1 | 2022-10-05 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). 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. 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 missense change has been observed in individual(s) with Niemann-Pick Type C (PMID: 11545687). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 63 of the NPC1 protein (p.Cys63Arg). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004690351 | SCV005185780 | uncertain significance | not specified | 2024-05-15 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.187T>C (p.Cys63Arg) results in a non-conservative amino acid change located in the Niemann-Pick C1, N-terminal domain (IPR032190) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250928 control chromosomes (gnomAD). c.187T>C has been reported in the literature at least in an individual affected with Niemann-Pick Disease Type C (e.g. Meiner_2001). These data indicate that the variant may be associated with disease. Functional studies suggest that this variant, affect NPC1 trafficking (Wang_2019, Wang_2020). The following publications have been ascertained in the context of this evaluation (PMID: 11545687, 31509197, 31699992). ClinVar contains an entry for this variant (Variation ID: 2138139). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |