Table 2 Description of the reported mutations in the NPC1 gene and the pathogenicity prediction scores

14 patients

c.2974 G > T

p.G992W

“point mutation”

missense

20

Homozygous

It was reported as pathogenic variant in Nova Scotia patients (reference 15). It is a point mutation that causes a G 2974 → T transversion which converts glycine 992 to tryptophan. It was found in 8 clones from two patients and was not observed in cDNAs derived from unaffected individuals. This single base change abolishes a Bsu361 restriction-enzyme recognition site

It was also reported as pathogenic in 2 Arab Muslim families in Israel (reference 7)

1 patient

Chr18:21120484 insC

c.2531dpG

p.V845Cfs*24

Novel

“frameshift: insertion mutation”

17

Homozygous

To our knowledge, it has not been reported previously, neither as a pathogenic nor as a benign one. We believe it is likely pathogenic because it introduces a premature stop codon at codon 869 which creates a premature translational stop signal. These changes may result in nonsense mediated mRNA decay as predicted by Mutation Taster (http://www.mutationtaster.org/)

This variant was not observed in 1000 genomes, ExAC, and gnomAD databases, indicating it is not a common benign variant in these populations

The variant was found to segregate with the disease phenotype in the family. Loss-of-function variants in NPC1 gene are known to be pathogenic

Based on the standards and guidelines of American College of Medical Genetics and Genomics (ACMGG), we assessed this variant as being pathogenic

1 patient

c.2780 C > T

A927V

“point mutation” missense

18

Homozygous

It was previously reported as pathogenic in an Arab

Muslim family in Israel (reference 7)