Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000003112 | SCV002210478 | pathogenic | Niemann-Pick disease, type C1 | 2022-08-25 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NPC1 function (PMID: 12554680). 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. ClinVar contains an entry for this variant (Variation ID: 2978). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 12554680). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 113 of the NPC1 protein (p.Cys113Arg). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002509143 | SCV002819764 | likely pathogenic | Niemann-Pick disease, type C | 2022-12-04 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.337T>C (p.Cys113Arg) 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 251388 control chromosomes. c.337T>C has been reported in the literature as a presumably de-novo occurrence resulting in a compound heterozygous genotype in at-least one individual affected with infantile NiemannPick type C disease (example, Blom_2003 with subsequent citations by others). At least one publication reports experimental evidence evaluating an impact on protein function demonstrating 1. increased accumulation of cholesterol in patient cells, 2. an inability of the mutant protein to reverse cholesterol accumulation in NPC1-deficient cells and 3. failure to localize correctly to late endocytic compartments and mislocalization to the ER. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| OMIM | RCV000003112 | SCV000023270 | pathogenic | Niemann-Pick disease, type C1 | 2003-02-01 | no assertion criteria provided | literature only |