ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3591+1G>A (rs786200877)

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Total submissions: 4
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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.
Invitae RCV000003107 SCV001586104 pathogenic Niemann-Pick disease type C1 2020-10-27 criteria provided, single submitter clinical testing 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). This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Niemann-Pick type C (PMID: 11479732, 31296176). This variant is also known as IVS23+1G>A. ClinVar contains an entry for this variant (Variation ID: 2973). Studies have shown that this variant alters NPC1 gene expression. (PMID: 11479732). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003107 SCV000023265 pathogenic Niemann-Pick disease type C1 2001-07-01 no assertion criteria provided literature only

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