ClinVar Genomic variation as it relates to human health
NM_000271.5(NPC1):c.2861C>T (p.Ser954Leu)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000271.5(NPC1):c.2861C>T (p.Ser954Leu)
Variation ID: 181457 Accession: VCV000181457.45
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q11.2 18: 23539405 (GRCh38) [ NCBI UCSC ] 18: 21119369 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Mar 29, 2015 Oct 20, 2024 Feb 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000271.5:c.2861C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000262.2:p.Ser954Leu missense NC_000018.10:g.23539405G>A NC_000018.9:g.21119369G>A NG_012795.1:g.52213C>T O15118:p.Ser954Leu - Protein change
- S954L
- Other names
-
p.S954L:TCG>TTG
- Canonical SPDI
- NC_000018.10:23539404:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00008
The Genome Aggregation Database (gnomAD) 0.00010
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
Help
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. |
|||
NPC1 | - | - |
GRCh38 GRCh37 |
2471 | 2529 |
Conditions - Germline
Condition
Help
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. |
---|---|---|---|---|
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000158972.24 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2022 | RCV000254670.29 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 9, 2019 | RCV001193400.2 | |
NPC1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 25, 2024 | RCV003407592.5 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893486.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(Jul 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362189.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: NPC1 c.2861C>T (p.Ser954Leu) 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.2861C>T (p.Ser954Leu) 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 7.6e-05 in 251102 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (7.6e-05 vs 0.0028), allowing no conclusion about variant significance. The variant, c.2861C>T, has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (e.g. Reunert_2016, Tarugi_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000770849.7
First in ClinVar: May 27, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 954 of the NPC1 protein (p.Ser954Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 954 of the NPC1 protein (p.Ser954Leu). This variant is present in population databases (rs543206298, gnomAD 0.03%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 11182931, 12401890, 23773996, 24915861, 26666848, 27581084). 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: 181457). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPC1 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Oct 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149856.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Observation 1:
Sex: male
Tissue: blood
Observation 2:
Sex: male
Tissue: blood
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446737.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hearing impairment (present) , Dementia (present) , Cerebellar ataxia (present) , Hand tremor (present)
Sex: female
|
|
Pathogenic
(Aug 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000208909.11
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21228398, 26338816, 26666848, 24676439, 32138288, 32071943, 25238906, 24915861, 10521290, 23773996, 25236789, 27544496, 28421028, 23433426, 31635081, 15465421, 32222928, 31980526, 34426522, 31589614, 33098801, 33624863) (less)
|
|
Pathogenic
(Jun 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003824110.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Niemann-Pick disease, type C1
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051891.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001335074.25
First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Jul 23, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220623.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Niemann-Pick disease type C1
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453838.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
Pathogenic
(Sep 25, 2024)
|
no assertion criteria provided
Method: clinical testing
|
NPC1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004114773.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The NPC1 c.2861C>T variant is predicted to result in the amino acid substitution p.Ser954Leu. This variant has been reported, along with another NPC1 variant, in … (more)
The NPC1 c.2861C>T variant is predicted to result in the amino acid substitution p.Ser954Leu. This variant has been reported, along with another NPC1 variant, in many unrelated individuals with Niemann-Pick type C disease (see examples: Greer et al. 1999. PubMed ID: 10521290; Bauer et al. 2013. PubMed ID: 23773996; Imrie et al. 2015. PubMed ID: 26666848; Dardis et al. 2020. PubMed ID: 32138288; Koens et al. 2016. PubMed ID: 27581084; Yamamoto et al. 2000. PubMed ID: 11182931; Zhang et al. 2014. PubMed ID: 24915861; Reunert et al. 2015. PubMed ID: 26981555). In vitro functional studies demonstrate that expression of this variant decelerates cholesterol clearance (Feng et al. 2019. PubMed ID: 31635081). This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD and has been consistently classified as pathogenic in ClinVar. This variant is interpreted as pathogenic. (less)
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Ataxia, dystonia and myoclonus in adult patients with Niemann-Pick type C. | Koens LH | Orphanet journal of rare diseases | 2016 | PMID: 27581084 |
Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening. | Reunert J | EBioMedicine | 2015 | PMID: 26981555 |
Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database. | Imrie J | BMC neurology | 2015 | PMID: 26666848 |
Observational, retrospective study of a large cohort of patients with Niemann-Pick disease type C in the Czech Republic: a surprisingly stable diagnostic rate spanning almost 40 years. | Jahnova H | Orphanet journal of rare diseases | 2014 | PMID: 25236789 |
Diagnosis of Niemann-Pick disease type C with 7-ketocholesterol screening followed by NPC1/NPC2 gene mutation confirmation in Chinese patients. | Zhang H | Orphanet journal of rare diseases | 2014 | PMID: 24915861 |
Niemann-Pick disease type C: a case series of Brazilian patients. | Lorenzoni PJ | Arquivos de neuro-psiquiatria | 2014 | PMID: 24676439 |
Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study. | Bauer P | Human molecular genetics | 2013 | PMID: 23773996 |
Niemann-Pick disease type C clinical database: cognitive and coordination deficits are early disease indicators. | Stampfer M | Orphanet journal of rare diseases | 2013 | PMID: 23433426 |
Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in fibroblasts. | Tarugi P | Journal of lipid research | 2002 | PMID: 12401890 |
Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts. | Yamamoto T | Journal of medical genetics | 2000 | PMID: 11182931 |
Text-mined citations for rs543206298 ...
HelpRecord last updated Oct 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.