ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000599506 SCV000709826 pathogenic not provided 2017-10-31 criteria provided, single submitter clinical testing The c.423_424dupGA variant in the NPC1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.423_424dupGA variant causes a frameshift starting with codon Lysine 142, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 80 of the new reading frame, denoted p.Lys142ArgfsX80. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.423_424dupGA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.423_424dupGA as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America 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.
Counsyl RCV000984200 SCV001132258 likely pathogenic Niemann-Pick disease type C1 2014-01-02 no assertion criteria provided clinical testing

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