ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2524T>C (p.Phe842Leu)

gnomAD frequency: 0.00017  dbSNP: rs190298665
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000596349 SCV000704660 uncertain significance not provided 2016-12-15 criteria provided, single submitter clinical testing
Invitae RCV000649025 SCV000770846 pathogenic Niemann-Pick disease, type C1 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 842 of the NPC1 protein (p.Phe842Leu). This variant is present in population databases (rs190298665, gnomAD 0.02%). This missense change has been observed in individuals with Niemann-Pick Disease Type C (PMID: 29453517; Invitae). ClinVar contains an entry for this variant (Variation ID: 499258). 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.Phe842 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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.
New York Genome Center RCV000649025 SCV002099149 uncertain significance Niemann-Pick disease, type C1 2021-04-02 criteria provided, single submitter clinical testing The c.2524T>C, p.Phe842Leu missense variant identified in NPC1 has been reported in trans with a pathogenic variant in a 31-year-old patient with Niemann-Pick disease type C [PMID: 29453517]. This variant has twenty nine heterozygous alleles in the gnomAD v3 database consistent with the carrier frequency and in silico tools predict a deleterious effect. Based on the available evidence, the variant c.2524T>C, p.Phe842Leu in the NPC1gene is classified as a variant of uncertain significance.
Revvity Omics, Revvity RCV000649025 SCV003816041 uncertain significance Niemann-Pick disease, type C1 2020-03-12 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003952965 SCV004767838 likely pathogenic NPC1-related disorder 2023-12-20 criteria provided, single submitter clinical testing The NPC1 c.2524T>C variant is predicted to result in the amino acid substitution p.Phe842Leu. This variant has been reported in the compound heterozygous state in an individual with adult-onset Niemann-Pick disease type C (Zeiger et al. 2018. PubMed ID: 29453517) and was also identified in the analysis of a large sequencing dataset that did not include individuals with Niemann-Pick disease (Wassif et al. 2015. PubMed ID: 25764212). Additionally, this variant was seen in the compound heterozygous state in a patient at PreventionGenetics with biochemical findings that confirmed the diagnosis of Niemann-Pick disease. In summary, we interpret this variant as likely pathogenic.
Natera, Inc. RCV000649025 SCV001455861 uncertain significance Niemann-Pick disease, type C1 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.