ClinVar Genomic variation as it relates to human health
NM_000271.5(NPC1):c.3011C>T (p.Ser1004Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic(4); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000271.5(NPC1):c.3011C>T (p.Ser1004Leu)
Variation ID: 326253 Accession: VCV000326253.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q11.2 18: 23538572 (GRCh38) [ NCBI UCSC ] 18: 21118536 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Apr 15, 2024 Feb 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000271.5:c.3011C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000262.2:p.Ser1004Leu missense NC_000018.10:g.23538572G>A NC_000018.9:g.21118536G>A NG_012795.1:g.53046C>T O15118:p.Ser1004Leu - Protein change
- S1004L
- Other names
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- Canonical SPDI
- NC_000018.10:23538571:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00047
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
The Genome Aggregation Database (gnomAD) 0.00066
The Genome Aggregation Database (gnomAD), exomes 0.00068
Exome Aggregation Consortium (ExAC) 0.00094
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NPC1 | - | - |
GRCh38 GRCh37 |
2442 | 2493 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 1, 2023 | RCV000414264.13 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000675137.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 28, 2024 | RCV003114486.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 12, 2024 | RCV003922387.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Apr 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800722.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Aug 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000704662.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Likely pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000407852.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163435.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Uncertain significance
(Jan 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490668.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
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, … (more)
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) (less)
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Likely pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000951601.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Uncertain significance
(Feb 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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NPC1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004742182.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
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, … (more)
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 (https://preview.ncbi.nlm.nih.gov/clinvar/variation/326253/). 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. (less)
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Likely pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004140857.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
NPC1: PM2, PM3, PM5, PP3, PS4:Supporting
Number of individuals with the variant: 2
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Uncertain significance
(Feb 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003800707.3
First in ClinVar: Feb 13, 2023 Last updated: Apr 15, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Niemann-Pick disease type C1
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453836.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Retinal axonal degeneration in Niemann-Pick type C disease. | Havla J | Journal of neurology | 2020 | PMID: 32222928 |
Phenotypic variability of Niemann-Pick disease type C including a case with clinically pure schizophrenia: a case report. | Kawazoe T | BMC neurology | 2018 | PMID: 30119649 |
Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders. | Zech M | PloS one | 2013 | PMID: 24386122 |
Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. | Park WD | Human mutation | 2003 | PMID: 12955717 |
Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. | Sun X | American journal of human genetics | 2001 | PMID: 11349231 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPC1 | - | - | - | - |
Text-mined citations for rs150334966 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.