ClinVar

Description

Variant summary: NPC1 c.3343G>T (p.Val1115Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 251462 control chromosomes, predominantly at a frequency of 0.0099 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3343G>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C without strong evidence of causality (Rodriguez_2015, Kubaski_2022). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. 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: 25989649, 35892469). ClinVar contains an entry for this variant (Variation ID: 92712). Based on the evidence outlined above, the variant was classified as likely benign.