ClinVar Miner

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

gnomAD frequency: 0.00066  dbSNP: rs150334966
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, 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 2020-01-21 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11349231, 24386122, 30119649, 32371106)
Eurofins Ntd Llc (ga) 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 likely pathogenic Niemann-Pick disease, type C1 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1004 of the NPC1 protein (p.Ser1004Leu). This variant is present in population databases (rs150334966, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 11349231, 30119649; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 326253). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. This variant disrupts the p.Ser1004 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 32222928), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV000675137 SCV001163435 likely pathogenic Niemann-Pick disease, type C1 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003114486 SCV003800707 uncertain significance not specified 2024-02-28 criteria provided, single submitter clinical testing Variant summary: NPC1 c.3011C>T (p.Ser1004Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 251486 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (0.00068 vs 0.0027), allowing no conclusion about variant significance. c.3011C>T has been reported in the literature as a biallelic compound heterozygous genotype in individuals with a clinically variable phenotype of Niemann-Pick disease type C (NPC) (example, Kawazoe_2018, Sun_2001). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30119649, 11349231). ClinVar contains an entry for this variant (Variation ID: 326253). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000414264 SCV004140857 likely pathogenic not provided 2023-03-01 criteria provided, single submitter clinical testing NPC1: PM2, PM3, PM5, PP3, PS4:Supporting
PreventionGenetics, part of Exact Sciences RCV003922387 SCV004742182 uncertain significance NPC1-related disorder 2024-02-12 criteria provided, single submitter clinical testing The NPC1 c.3011C>T variant is predicted to result in the amino acid substitution p.Ser1004Leu. This variant has been reported in patients with Niemann-Pick disease, however, its pathogenicity was not completely elucidated (Sun et al. 2001. PubMed ID: 11349231; Kawazoe et al. 2018. PubMed ID: 30119649). This variant is reported in 0.15% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretation in ClinVar ranging from uncertain to likely pathogenic ( Of note, a different variant impacting the same amino acid (p.Ser1004Pro) has been documented in patients with NPC1-related disorder (Supplemental Table 1 in Reunert. 2016. PubMed ID: 26981555). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc. RCV000675137 SCV001453836 uncertain significance Niemann-Pick disease, type C1 2020-09-16 no assertion criteria provided clinical testing

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