ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1628C>T (p.Pro543Leu) (rs369368181)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000158970 SCV000220410 likely pathogenic Niemann-Pick disease type C1 2014-06-14 criteria provided, single submitter literature only
Fulgent Genetics,Fulgent Genetics RCV000158970 SCV000611220 pathogenic Niemann-Pick disease type C1 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000158970 SCV000650835 likely pathogenic Niemann-Pick disease type C1 2017-07-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 543 of the NPC1 protein (p.Pro543Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous or in combination with other pathogenic variants in the NPC1 gene in individuals affected with  Niemann-Pick Type C disease (PMID: 12955717, 16126423, 19744920, 22476655, 22676771). ClinVar contains an entry for this variant (Variation ID: 181455). 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. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000610038 SCV000731399 pathogenic Niemann-Pick disease, type C 2017-02-14 criteria provided, single submitter clinical testing The p.Pro543Leu (NM_000271.4 c.1628C>T) variant in NPC1 has been reported in 1 h omozygous and 4 compound heterozygous individuals with Niemann-Pick disease type C (Millat 2005, Garver 2010, Heron 2012, and Chien 2013). This variant is absen t from ExAC but has been identified in 1/8,600 of European chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs3693681 81). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease type C in an autosomal recessive manner based upon its bial lelic occurrence in patients and low frequency in controls.

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