Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000670704 | SCV000795594 | uncertain significance | Niemann-Pick disease, type C1 | 2017-11-09 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000670704 | SCV002238575 | pathogenic | Niemann-Pick disease, type C1 | 2023-10-14 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 789 of the NPC1 protein (p.Arg789Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NPC1-related conditions (PMID: 11349231). ClinVar contains an entry for this variant (Variation ID: 554973). 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 disrupts the p.Arg789 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24915861). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317331 | SCV004020536 | uncertain significance | not specified | 2023-06-27 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.2365C>T (p.Arg789Cys) results in a non-conservative amino acid change located in the Sterol-sensing domain (IPR000731) 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 251460 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2365C>T has been reported in the literature in a cell line isolated from a patient with classical biochemical phenotype (example: Sun_2001). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 11349231). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |