ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1628C>T (p.Pro543Leu)

gnomAD frequency: 0.00001  dbSNP: rs369368181
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000158970 SCV000220410 likely pathogenic Niemann-Pick disease, type C1 2014-06-14 criteria provided, single submitter literature only
Fulgent Genetics, Fulgent Genetics RCV000158970 SCV000611220 pathogenic Niemann-Pick disease, type C1 2021-10-22 criteria provided, single submitter clinical testing
Invitae RCV000158970 SCV000650835 pathogenic Niemann-Pick disease, type C1 2023-12-25 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 543 of the NPC1 protein (p.Pro543Leu). This variant is present in population databases (rs369368181, gnomAD 0.01%). This missense change has been observed in individuals with Niemann-Pick Type C disease (PMID: 12955717, 16126423, 19744920, 22476655, 22676771). ClinVar contains an entry for this variant (Variation ID: 181455). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000610038 SCV000731399 pathogenic Niemann-Pick disease, type C 2017-02-14 criteria provided, single submitter clinical testing The p.Pro543Leu (NM_000271.4 c.1628C>T) variant in NPC1 has been reported in 1 h omozygous and 4 compound heterozygous individuals with Niemann-Pick disease type C (Millat 2005, Garver 2010, Heron 2012, and Chien 2013). This variant is absen t from ExAC but has been identified in 1/8,600 of European chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs3693681 81). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease type C in an autosomal recessive manner based upon its bial lelic occurrence in patients and low frequency in controls.

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.