Submissions for variant NM_000271.5(NPC1):c.1819C>T (p.Arg607Ter)

dbSNP: rs377130051

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255864	SCV000322457	pathogenic	not provided	2015-12-17	criteria provided, single submitter	clinical testing	The R607X pathogenic variant in the NPC1 gene has been reported previously in association with Niemann-Pick Disease Type C, in an affected individual who was compound heterozygous for the R607X pathogenic variant and another variant (Bauer et al., 2002). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R607X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R607X as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589541	SCV000696415	pathogenic	Niemann-Pick disease, type C	2017-08-02	criteria provided, single submitter	clinical testing	Variant summary: The c.1819C>T (p.Arg607*) variant in NPC1 gene is a nonsense change that results in the loss of the 677 amino acids of the protein (~52%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay and truncated protein that would be translated from this allele was not detected by western blot (Zampieri, 2013). The variant is absent from in the large control population dataset of ExAC (121384 chrs tested). The variant has been identified in compound heterozygosity with known pathogenic alleles in several affected individuals presented with the classical biochemical phenotype NPC-1 characterized by massive lysosomal/ LE accumulation of unesterified cholesterol in cultured fibroblasts. Taken together, the variant was classified as Pathogenic.
Ambry Genetics	RCV001265830	SCV001444002	pathogenic	Inborn genetic diseases	2021-05-18	criteria provided, single submitter	clinical testing	The c.1819C>T (p.R607*) alteration, located in coding exon 12 of the NPC1 gene, results from a C to T substitution at nucleotide position 1819. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 607. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the NPC1 c.1819C>T alteration was observed in 0.003% (1/31,382) of total alleles studied, with a frequency of 0.12% (1/848) in the Latino subpopulation. This alteration has been reported in a patient with Niemann-Pick type C based on filipin staining of cholesterol and bone marrow cytology (Bauer, 2002). Parental testing confirmed that the alteration was in trans with a >23 kb deletion in NPC1. Based on the available evidence, this alteration is classified as pathogenic.
Invitae	RCV001273179	SCV003280049	pathogenic	Niemann-Pick disease, type C1	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg607*) 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 present in population databases (no rsID available, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick type C (PMID: 11754101, 32138288). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265495). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc.	RCV001273179	SCV001455871	pathogenic	Niemann-Pick disease, type C1	2020-09-16	no assertion criteria provided	clinical testing