Submissions for variant NM_000271.5(NPC1):c.3718G>A (p.Gly1240Arg)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003236400	SCV003934418	likely pathogenic	Niemann-Pick disease, type C	2023-05-24	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3718G>A (p.Gly1240Arg) 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 4e-06 in 251446 control chromosomes. c.3718G>A has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Niemann-Pick Disease Type C or acute liver failure (Runz_2008, Chamova_2016, LopezdeFrutos_2020, Hegarty_2021). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, showing the variant is reponsive to cholesterol-lowering treatments (Pipalia_2017). The following publications have been ascertained in the context of this evaluation (PMID: 26910362, 34023347, 32745579, 28193631, 18081003). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.