Submissions for variant NM_000271.5(NPC1):c.3175C>T (p.Arg1059Ter)

dbSNP: rs786204455

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169092	SCV000220277	likely pathogenic	Niemann-Pick disease, type C1	2014-04-29	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201288	SCV001372413	pathogenic	Niemann-Pick disease, type C	2020-06-04	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3175C>T (p.Arg1059X) results in a premature termination codon. This variant has been shown to result in nonsense-mediated decay in patient fibroblasts (Macias-Vidal_2009). Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251422 control chromosomes. c.3175C>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (Fernandez-Valero_2005, Imrie_2015). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169092	SCV003442579	pathogenic	Niemann-Pick disease, type C1	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1059*) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type C (PMID: 16098014, 26666848). ClinVar contains an entry for this variant (Variation ID: 188769). For these reasons, this variant has been classified as Pathogenic.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000169092	SCV000536736	pathogenic	Niemann-Pick disease, type C1	2015-09-29	no assertion criteria provided	research
Natera, Inc.	RCV000169092	SCV002095168	pathogenic	Niemann-Pick disease, type C1	2021-03-22	no assertion criteria provided	clinical testing