ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.973_974dup (p.Asp325fs) (rs886044580)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000480305 SCV000345567 pathogenic not provided 2016-08-25 criteria provided, single submitter clinical testing
GeneDx RCV000480305 SCV000568736 pathogenic not provided 2017-02-22 criteria provided, single submitter clinical testing The c.973_974dupGA variant in the NPC1 gene has been reported previously in association with Niemann-Pick disease type C (alternate nomenclature as c.974_975insGA; Park et al., 2013). The c.973_974dupGA variant causes a frameshift starting with codon Aspartic Acid 325, changes this amino acid to a Glutamic Acid residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Asp325GlufsX12. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.973_974dupGA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.973_974dupGA as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV001260390 SCV001437352 pathogenic Niemann-Pick disease, type C 2020-09-21 criteria provided, single submitter clinical testing Variant summary: NPC1 c.973_974dupGA (p.Asp325GlufsX12) 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. The variant was absent in 250156 control chromosomes. c.973_974dupGA has been reported in the literature in studies examining individuals affected with Niemann-Pick Disease Type C and also subsequently cited by others (example, Park_2003, Garver_2010, Cologna_2014). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported although this variant was included in a study that examined the markers of neuroinflammation in human post-mortem NPC1 brain tissues (Cologna_2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000984202 SCV001132262 likely pathogenic Niemann-Pick disease type C1 2016-11-18 no assertion criteria provided clinical testing
Natera, Inc. RCV000984202 SCV001455878 pathogenic Niemann-Pick disease type C1 2020-09-16 no assertion criteria provided clinical testing

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