ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.423_424dup (p.Lys142fs) (rs773941375)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000599506 SCV000709826 pathogenic not provided 2019-09-16 criteria provided, single submitter clinical testing Identified using alternate nomenclature c.424_425insGA in a cohort of individuals with biochemically confirmed Niemann-Pick disease type C, however, the number of individuals harboring this variant and additional clinical information was not provided (Park et al., 2003); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12955717)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193397 SCV001362185 likely pathogenic Niemann-Pick disease, type C 2019-04-11 criteria provided, single submitter clinical testing Variant summary: NPC1 c.423_424dupGA (p.Lys142ArgfsX80) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2972_2973delAG (p.Gln991fsX15), c.3742_3745delCTCA (p.Leu1248fsX3)). The variant allele was found at a frequency of 1.1e-05 in 277192 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (Mazzacuva_2016, Park_2003). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000984200 SCV001579550 pathogenic Niemann-Pick disease type C1 2020-09-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys142Argfs*80) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs773941375, ExAC 0.001%). This variant has been observed in individual(s) with Niemann-Pick Disease Type C (PMID: 12955717). ClinVar contains an entry for this variant (Variation ID: 503633). Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000984200 SCV001132258 likely pathogenic Niemann-Pick disease type C1 2014-01-02 no assertion criteria provided clinical testing

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