ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1843C>T (p.Arg615Cys) (rs745777805)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000685980 SCV000813483 uncertain significance Niemann-Pick disease type C1 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 615 of the NPC1 protein (p.Arg615Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs745777805, ExAC 0.01%). This variant has been observed in individuals affected with Niemann-Pick disease type C (PMID: 26666848). ClinVar contains an entry for this variant (Variation ID: 566223). 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.Arg615 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 17160617), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV001193402 SCV001362191 likely pathogenic Niemann-Pick disease, type C 2019-10-28 criteria provided, single submitter clinical testing Variant summary: NPC1 c.1843C>T (p.Arg615Cys) results in a non-conservative amino acid change located in the Domian C (lumenal domain, Gong_2016) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251472 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (5.2e-05 vs 0.0028), allowing no conclusion about variant significance. c.1843C>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (Imrie_2006, Imrie_2015, Nadjar_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as uncertain significance. In addition, other variants affecting this codon (p.R615H, p.R615L) have been reported in NPC patients (HGMD database). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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