Niemann-Pick Type C Disease (NP-C; OMIM#257220; OMIM#607625) is a rare autosomal-recessive lysosomal storage disorder which severely affects the nervous system and may cause enlargement of liver and spleen. The clinical spectrum of NP-C is highly variably and includes a wide range of neurological, psychiatric and visceral symptoms. Niemann-Pick type C disease (NP-C) is caused by mutations in either the NPC1 or NPC2 gene.
The NPC1 gene is located on chromosome 18q11-12 and encodes for a large membranous glycoprotein (1278 amino acids) in the late endosomes and lysosomes. It consists of 25 exons and spans over approximately 47 kilobases. The NPC2 gene, a much smaller gene, which encodes a small, soluble, lysosomal protein (132 amino acids) with cholesterol binding properties, contains only 5 exons and spans over 13,5 kilobases. It has been mapped to 14q24.3
Although two causative genes have been identified, making the final diagnosis NP-C remains difficult. Beside a few common mutations in the NPC1 gene, many patients present with rare variants and there is often no further information about their effects. Even though the number of functional studies is limited, we have gained new information about the occurrence of rare variants in the NPC1 and NPC2 gene in healthy control populations (i.e. 1000G, ExaC etc).
We have used this information as well as our collection of variants from NP-C patients to create a database that covers benign as well as pathogenic variants in NPC1 and NPC2. By relaunching a newly, updated version of the NPC-db variation database, we intend to facilitate the evaluation of NP-C variants and create a modern tool that supports diagnosticians in their evaluation of a suspected NP-C patient.
Each variant is classified into one of five categories. Ranging from class 1 = probably benign variant over class 3 = variant of unknown significance to class 5 = probably pathogenic variant. The classification is based on clinical data, published data and control study cohorts. The variant list includes the count of patients and controls. We also provide information on the allele frequencies in different control cohorts. The source of the data can be found by clicking on a variant . As we are collaborators in the International Niemann-Pick Disease registry we aim to intertwine both registries, thus securing an ongoing input of information on the number and types of variants found in actual NP-C patients.
We believe that this updated database will be a unique tool to evaluate variants in patients suspected for NP-C and the information will support researchers in their pursuit of learning more about the genetic variations of NP-C.
• The genomic coordinates of the variants refer to the hg19 reference genome.
• NPC1 variant annotations are based on the NM_000271.4 transcript.
• NPC2 variant annotations are based on the NM_006432.3 transcript.