Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000649023 | SCV000770844 | likely pathogenic | Niemann-Pick disease, type C1 | 2024-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 945 of the NPC1 protein (p.Asp945Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with biochemical features of Niemann-Pick Type C (PMID: 12955717, 19744920; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 539312). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002509492 | SCV002819470 | likely pathogenic | Niemann-Pick disease, type C | 2022-12-02 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.2833G>A (p.Asp945Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250474 control chromosomes (gnomAD). c.2833G>A has been reported in the literature in individuals affected with Niemann-Pick Disease Type C and was reported to cause 'severe' biochemical phenotype (Park_2003, Garver_2010, Ribas_2016, Lopez de Frutos_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function, demonstrated the variant to cause a reduction in total protein expression and result in protein of distinct molecular weights, one equivalent to the wild type and the other equivalent to that found in lower-molecular-weight mutants. Furthermore, the variant showed defective cholesterol trafficking. Taken together, the authors concluded the variant to be pathogenic (Erwood_2019). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Natera, |
RCV000649023 | SCV001453840 | uncertain significance | Niemann-Pick disease, type C1 | 2020-09-16 | no assertion criteria provided | clinical testing |