ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3591+1G>A

gnomAD frequency: 0.00001  dbSNP: rs786200877
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
Counsyl RCV000003107 SCV000220771 likely pathogenic Niemann-Pick disease, type C1 2014-10-07 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193398 SCV001362186 pathogenic Niemann-Pick disease, type C 2019-08-26 criteria provided, single submitter clinical testing Variant summary: NPC1 c.3591+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in an unstable protein from two possible transcripts (Ribeiro_2001). The variant allele was found at a frequency of 1.2e-05 in 249950 control chromosomes. c.3591+1G>A has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (Ribeiro_2001, Park_2003, Stampfer_2013). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000003107 SCV001586104 pathogenic Niemann-Pick disease, type C1 2023-07-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that disruption of this splice site alters NPC1 gene expression (PMID: 11479732). ClinVar contains an entry for this variant (Variation ID: 2973). This variant is also known as IVS23+1G>A. Disruption of this splice site has been observed in individuals with Niemann-Pick type C (PMID: 11479732, 31296176). This variant is present in population databases (rs786200877, gnomAD 0.004%). This sequence change affects a donor splice site in intron 23 of the NPC1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850).
OMIM RCV000003107 SCV000023265 pathogenic Niemann-Pick disease, type C1 2001-07-01 no assertion criteria provided literature only
Natera, Inc. RCV000003107 SCV002095159 pathogenic Niemann-Pick disease, type C1 2020-05-15 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.