ClinVar Genomic variation as it relates to human health
NM_000271.5(NPC1):c.3467A>G (p.Asn1156Ser)
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
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NM_000271.5(NPC1):c.3467A>G (p.Asn1156Ser)
Variation ID: 2959 Accession: VCV000002959.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q11.2 18: 23535479 (GRCh38) [ NCBI UCSC ] 18: 21115443 (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 Apr 4, 2013 Mar 30, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000271.5:c.3467A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000262.2:p.Asn1156Ser missense NC_000018.10:g.23535479T>C NC_000018.9:g.21115443T>C NG_012795.1:g.56139A>G O15118:p.Asn1156Ser - Protein change
- N1156S
- Other names
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- Canonical SPDI
- NC_000018.10:23535478:T:C
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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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 |
2460 | 2518 |
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
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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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 21, 2024 | RCV000003093.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV003114174.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 3, 2022 | RCV003480016.1 |
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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Pathogenic
(Jun 03, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226691.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PP4, PM2, PM3, PM5, PS3, PS4
Number of individuals with the variant: 1
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Pathogenic
(Jan 21, 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: SCV000957635.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1156 of the NPC1 protein (p.Asn1156Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1156 of the NPC1 protein (p.Asn1156Ser). This variant is present in population databases (rs28942105, gnomAD 0.004%). This missense change has been observed in individuals with Niemann-Pick type C (PMID: 9211849, 16098014, 17160617, 23430855, 26666848, 27900365, 28710748). ClinVar contains an entry for this variant (Variation ID: 2959). 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.Asn1156 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 9211849, 16098014, 17160617, 23430855, 26666848, 27900365), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV001163433.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003800706.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: NPC1 c.3467A>G (p.Asn1156Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: NPC1 c.3467A>G (p.Asn1156Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248932 control chromosomes. c.3467A>G has been reported in the literature as a biallelic homozygous or compound heterozygous genotype in multiple individuals affected with Niemann-Pick Disease Type C (example, PMID: 9211849, 19744920, 26981555, 12401890). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 01, 2016)
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no assertion criteria provided
Method: clinical testing
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NPC1
Affected status: yes
Allele origin:
germline
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Shendure Lab, University of Washington
Accession: SCV000297806.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
patient had late-onset NPC
Age: 30-39 years
Sex: male
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Pathogenic
(Jul 11, 1997)
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no assertion criteria provided
Method: literature only
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NIEMANN-PICK DISEASE, TYPE C1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023251.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 30, 2024 |
Comment on evidence:
In each of 2 unrelated patients with Niemann-Pick disease (NPC1; 257220), Carstea et al. (1997) found compound heterozygosity at the NPC1 locus with one of … (more)
In each of 2 unrelated patients with Niemann-Pick disease (NPC1; 257220), Carstea et al. (1997) found compound heterozygosity at the NPC1 locus with one of the mutations being a 3467A-G transition, resulting in an asn1156-to-ser amino acid substitution in the NPC1 protein. The authors noted that asn1156 is conserved in human, mouse, C. elegans, and S. cerevisiae orthologs of NPC1. (less)
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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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Molecular Genetics of Niemann-Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants. | Dardis A | Journal of clinical medicine | 2020 | PMID: 32138288 |
Longitudinal Changes in White Matter Fractional Anisotropy in Adult-Onset Niemann-Pick Disease Type C Patients Treated with Miglustat. | Bowman EA | JIMD reports | 2018 | PMID: 28710748 |
Genome sequencing in a case of Niemann-Pick type C. | Dougherty M | Cold Spring Harbor molecular case studies | 2016 | PMID: 27900365 |
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 |
Niemann-Pick Disease Type C Presenting as a Developmental Coordination Disorder with Bullying by Peers in a School-Age Child. | Suzuki R | Case reports in pediatrics | 2015 | PMID: 26788393 |
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 |
[Niemann-Pick type C disease and psychosis: Two siblings]. | Maubert A | L'Encephale | 2015 | PMID: 25238906 |
The proteasome inhibitor bortezomib reduced cholesterol accumulation in fibroblasts from Niemann-Pick type C patients carrying missense mutations. | Macías-Vidal J | The FEBS journal | 2014 | PMID: 25131710 |
Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders. | Zech M | PloS one | 2013 | PMID: 24386122 |
Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking. | Zampieri S | JIMD reports | 2012 | PMID: 23430855 |
The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes. | Garver WS | Journal of lipid research | 2010 | PMID: 19744920 |
The natural history of Niemann-Pick disease type C in the UK. | Imrie J | Journal of inherited metabolic disease | 2007 | PMID: 17160617 |
Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations. | Fernandez-Valero EM | Clinical genetics | 2005 | PMID: 16098014 |
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 |
Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. | Carstea ED | Science (New York, N.Y.) | 1997 | PMID: 9211849 |
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Text-mined citations for rs28942105 ...
HelpRecord last updated Mar 30, 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.