Submissions for variant NM_000271.5(NPC1):c.1042C>T (p.Arg348Ter)

dbSNP: rs1474434210

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001935139	SCV002176668	pathogenic	Niemann-Pick disease, type C1	2023-07-16	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1405310). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with Niemann-Pick type C (PMID: 26981555, 27549128). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg348*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226501	SCV003922607	pathogenic	Niemann-Pick disease, type C	2023-03-16	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.1042C>T (p.Arg348X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250764 control chromosomes (gnomAD). c.1042C>T has been reported in the literature in individuals affected with Niemann-Pick Disease (example: Sztolsztener _2010, Reunert_2016, Cervera-Gaviria_2016). 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 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001935139	SCV005044820	pathogenic	Niemann-Pick disease, type C1		criteria provided, single submitter	clinical testing	The stop gained variant c.1042C>Tp.Arg348Ter in NPC1 gene has been reported in compound heterozygous state in multiple individulas affected with Niemann-Pick disease, type C1 Cervera-Gaviria et. al., 2016; Reunert et. al., 2015. The c.1042C>T variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.1042C>T in NPC1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in NPC1 are known to be Pathogenic Loftus et. al., 1997. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV004591626	SCV005078880	likely pathogenic	not provided	2023-12-09	criteria provided, single submitter	clinical testing	Observed with a second variant in the NPC1 gene in a patient with Niemann-Pick disease type C from a family in which paternal gonadal mosaicism was suspected (PMID: 27549128); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19900398, 22286891, 24386122, 25349751, 26981555, 27549128)