ClinVar Genomic variation as it relates to human health

The c.2524T>C, p.Phe842Leu missense variant identified in NPC1 has been reported in trans with a pathogenic variant in a 31-year-old patient with Niemann-Pick disease type C [PMID: 29453517]. This variant has twenty nine heterozygous alleles in the gnomAD v3 database consistent with the carrier frequency and in silico tools predict a deleterious effect. Based on the available evidence, the variant c.2524T>C, p.Phe842Leu in the NPC1gene is classified as a variant of uncertain significance.

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 842 of the NPC1 protein (p.Phe842Leu). This variant is present in population databases (rs190298665, gnomAD 0.02%). This missense change has been observed in individuals with Niemann-Pick Disease Type C (PMID: 29453517; Invitae). ClinVar contains an entry for this variant (Variation ID: 499258). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. This variant disrupts the p.Phe842 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Variant summary: NPC1 c.2524T>C (p.Phe842Leu) results in a non-conservative amino acid change in 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 3.6e-05 in 251096 control chromosomes (gnomAD). c.2524T>C has been reported in the literature in individuals affected with Niemann-Pick disease, type C1 (Wassif_2015, Mazzacuva_2016, Zeiger_2018, Rodriguez-Gil_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27139891, 34296265, 25764212, 29453517). ClinVar contains an entry for this variant (Variation ID: 499258). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

The NPC1 c.2524T>C variant is predicted to result in the amino acid substitution p.Phe842Leu. This variant has been reported in the compound heterozygous state in an individual with adult-onset Niemann-Pick disease type C (Zeiger et al. 2018. PubMed ID: 29453517) and was also identified in the analysis of a large sequencing dataset that did not include individuals with Niemann-Pick disease (Wassif et al. 2015. PubMed ID: 25764212). Additionally, this variant was seen in the compound heterozygous state in a patient at PreventionGenetics with biochemical findings that confirmed the diagnosis of Niemann-Pick disease. In summary, we interpret this variant as likely pathogenic.