ClinVar Miner

Submissions for variant NM_006432.4(NPC2):c.133C>T (p.Gln45Ter) (rs80358262)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000020643 SCV000914646 likely pathogenic Niemann-Pick disease, type C2 2018-08-17 criteria provided, single submitter clinical testing The NPC2 c.133C>T (p.Gln45Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gln45Ter variant has been reported in at least two studies in which it is found in a homozygous state in a total of two patients with Niemann-Pick Disease type C (NPC) (Chikh et al. 2005; Boenzi et al. 2014). Control data is unavailable for the p.Gln45Ter variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database, in a region of good sequence coverage, and hence is presumed to be rare. Functional studies using patient-derived fibroblasts isolated from two patients demonstrated that the p.Gln45Ter variant affected intracellular cholesterol processing to the degree previously associated with classic NPC (Chikh et al. 2005; Boenzi et al. 2014). Additionally, LC-MS/MS testing of the p.Gln45Ter patient-derived plasma oxysterols revealed pathogenic levels of C-triol and 7-KC compared to normal controls (Boenzi et al. 2014). Based on the collective evidence, the p.Gln45Ter variant is classified as likely pathogenic for Niemann-Pick Disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193595 SCV001362525 pathogenic Niemann-Pick disease, type C 2019-09-23 criteria provided, single submitter clinical testing Variant summary: NPC2 c.133C>T (p.Gln45X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 236558 control chromosomes (gnomAD). The variant, c.133C>T, has been reported in the literature in two homozygous individuals affected with Niemann-Pick Disease Type C (Vanier_2004, Chikh_2005, Boenzi_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000020643 SCV000041166 pathologic Niemann-Pick disease, type C2 2008-07-22 no assertion criteria provided curation Converted during submission to Pathogenic.

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