ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1210C>T (p.Arg404Trp) (rs1298238512)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727099 SCV000705676 likely pathogenic not provided 2017-01-17 criteria provided, single submitter clinical testing
Invitae RCV000593107 SCV000770847 likely pathogenic Niemann-Pick disease type C1 2019-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 404 of the NPC1 protein (p.Arg404Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Niemann-Pick type C disease (PMID: 12955717, 26981555). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg404 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27581084, 26666848, 11545687, 11349231, 22065762). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000593107 SCV000796805 uncertain significance Niemann-Pick disease type C1 2018-01-02 no assertion criteria provided clinical testing

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