Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000597242 | SCV000706422 | uncertain significance | not provided | 2017-02-17 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001377830 | SCV001575265 | pathogenic | Niemann-Pick disease, type C1 | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 101 of the NPC1 protein (p.Phe101Cys). This variant is present in population databases (rs548191894, gnomAD 0.02%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 26981555; Invitae). 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: 500461). 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%. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002222562 | SCV002500677 | uncertain significance | not specified | 2022-03-28 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.302T>G (p.Phe101Cys) 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 allele was found at a frequency of 2.4e-05 in 251334 control chromosomes (gnomAD). c.302T>G has been reported in the literature in compound heterozygous individuals affected with Niemann-Pick Disease Type C (Reunert_2016, and Panigrahi_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic (n=1), and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV001377830 | SCV004171361 | likely pathogenic | Niemann-Pick disease, type C1 | criteria provided, single submitter | clinical testing |