ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3011C>T (p.Ser1004Leu) (rs150334966)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000675137 SCV000407852 likely pathogenic Niemann-Pick disease type C1 2017-04-27 criteria provided, single submitter clinical testing The NPC1 gene c.3011C>T (p.Ser1004Leu) variant is a missense variant that is reported in two studies and found in a total of three individuals, including a sibling pair, with Niemann-Pick disease (NPC), all in a compound heterozygous state (Sun et al. 2001; Kawazoe et al. 2018). In the sibling pair, the p.Ser1004Leu variant was inherited from an unaffected father and was in trans with a frameshift variant inherited from the mother (Kawazoe et al. 2018). Control data are not available but the variant is reported at a frequency of 0.002268 in the European (Finnish) population of the Exome Aggregation Consortium. The Ser 1004 residue is located within the cysteine-rich region of the protein. Filipin staining of skin fibroblasts from one of the patients showed a staining pattern associated with NPC (Kawazoe et al. 2018). The evidence for this variant is limited. The p.Ser1004Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Niemann-Pick disease.
GeneDx RCV000414264 SCV000490668 uncertain significance not provided 2017-07-25 criteria provided, single submitter clinical testing The S1004L missense variant in the NPC1 gene has been reported previously in an individual with NPC who was also heterozygous for another variant in the NPC1 gene (Sun et al., 2001). Although the cholesterol esterification rate was normal, this individual was described as having classical symptoms of NPC and showed abnormal lactosylceramide trafficking in fibroblasts similar to classical NPC patients (Sun et al., 2001). The S1004L variant is observed in 15/6,614 (0.23%) alleles from individuals of Finnish European background in the ExAC dataset (Lek et al., 2016). The S1004L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (F995L, M996R, M1001T/V, P1007A/R/L, G1012D) have been reported in the Human Gene Mutation Database in association with NPC (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret S1004L as a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000414264 SCV000704662 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing
Counsyl RCV000675137 SCV000800722 uncertain significance Niemann-Pick disease type C1 2017-04-11 criteria provided, single submitter clinical testing
Invitae RCV000675137 SCV000951601 uncertain significance Niemann-Pick disease type C1 2019-06-03 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1004 of the NPC1 protein (p.Ser1004Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs150334966, ExAC 0.2%). This variant has been observed in individuals affected with Niemann-Pick disease (PMID: 11349231, 30119649). ClinVar contains an entry for this variant (Variation ID: 326253). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics RCV000675137 SCV001163435 likely pathogenic Niemann-Pick disease type C1 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.