ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1436G>A (p.Cys479Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1555636659
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000649020 SCV000770841 pathogenic Niemann-Pick disease, type C1 2024-12-24 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 479 of the NPC1 protein (p.Cys479Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 16098014, 20718790; 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: 539310). 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%. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga) RCV000728564 SCV000856156 uncertain significance not provided 2017-08-10 criteria provided, single submitter clinical testing
Baylor Genetics RCV000649020 SCV001163439 likely pathogenic Niemann-Pick disease, type C1 criteria provided, single submitter clinical testing
Ambry Genetics RCV003243238 SCV003965413 likely pathogenic Inborn genetic diseases 2023-03-30 criteria provided, single submitter clinical testing The c.1436G>A (p.C479Y) alteration is located in coding exon 9 of the NPC1 gene. This alteration results from a G to A substitution at nucleotide position 1436, causing the cysteine (C) at amino acid position 479 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in a Spanish child who developed generalized seizures at age 9 and was later diagnosed with Niemann-Pick disease type C at age 11. The child was heterozygous for this variant and a second mutation was not able to be detected (Fernandez-Valero 2005; Macías-Vidal 2011). This variant was also reported in trans with a second NPC1 mutation (p.A1054T c.3160G>A) in another Spanish child with severe infantile onset (Macías-Vidal 2011). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Natera, Inc. RCV000649020 SCV001455874 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.