ClinVar

Description

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.