Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000278598 | SCV000340176 | uncertain significance | not provided | 2016-03-23 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001859651 | SCV002316441 | likely pathogenic | Niemann-Pick disease, type C1 | 2023-12-11 | 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 1186 of the NPC1 protein (p.Arg1186Cys). This variant is present in population databases (rs145297180, gnomAD 0.003%). 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: 286652). 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.Arg1186 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9211849, 22326530, 26666848, 28105569). 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. |
| Ambry Genetics | RCV002519245 | SCV003734942 | uncertain significance | Inborn genetic diseases | 2022-03-07 | criteria provided, single submitter | clinical testing | The c.3556C>T (p.R1186C) alteration is located in exon 23 (coding exon 23) of the NPC1 gene. This alteration results from a C to T substitution at nucleotide position 3556, causing the arginine (R) at amino acid position 1186 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226275 | SCV003922602 | uncertain significance | not specified | 2023-03-17 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.3556C>T (p.Arg1186Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251042 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3556C>T in individuals affected with Niemann-Pick Disease Type C and no experimental evidence demonstrating its impact on protein function have been reported. Other alterations of this amino acid have been classified as pathogenic in ClinVar (p.R1186 and p.R1186H), suggesting an important role for this Amino Acid, however the available evidence is currently insufficient to determine the role of this variant in disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=2) and Likely Pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Laboratory of Medical Genetics, |
RCV001859651 | SCV005051889 | likely pathogenic | Niemann-Pick disease, type C1 | 2024-02-01 | criteria provided, single submitter | curation |