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

dbSNP: rs745777805

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685980	SCV000813483	pathogenic	Niemann-Pick disease, type C1	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 615 of the NPC1 protein (p.Arg615Cys). This variant is present in population databases (rs745777805, gnomAD 0.01%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 26666848). ClinVar contains an entry for this variant (Variation ID: 566223). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Ambry Genetics	RCV001265829	SCV001444001	pathogenic	Inborn genetic diseases	2021-05-18	criteria provided, single submitter	clinical testing	The c.1843C>T (p.R615C) alteration is located in coding exon 12 of the NPC1 gene. This alteration results from a C to T substitution at nucleotide position 1843, causing the arginine (R) at amino acid position 615 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD) database, the NPC1 c.1843C>T alteration was observed in 0.005% (13/251,472) of total alleles studied, with a frequency of 0.011% (2/18,394) in the East Asian subpopulation. This alteration has been reported in multiple unrelated patients with Niemann-Pick type C, confirmed by abnormal filipin staining and/or abnormal cholesterol esterification (Park, 2003; Imrie, 2015; Nadjar, 2018; Havla, 2020). This amino acid position is highly conserved in available vertebrate species. The p.R615C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000685980	SCV001554477	likely pathogenic	Niemann-Pick disease, type C1	2021-04-07	criteria provided, single submitter	clinical testing