ClinVar Genomic variation as it relates to human health
NM_006432.5(NPC2):c.352G>T (p.Glu118Ter)
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_006432.5(NPC2):c.352G>T (p.Glu118Ter)
Variation ID: 8480 Accession: VCV000008480.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.3 14: 74484426 (GRCh38) [ NCBI UCSC ] 14: 74951129 (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 Feb 14, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006432.5:c.352G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006423.1:p.Glu118Ter nonsense NM_001363688.1:c.352G>T NP_001350617.1:p.Glu118Ter nonsense NM_001375440.1:c.352G>T NP_001362369.1:p.Glu118Ter nonsense NC_000014.9:g.74484426C>A NC_000014.8:g.74951129C>A NG_007117.1:g.13956G>T - Protein change
- E118*
- Other names
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- Canonical SPDI
- NC_000014.9:74484425:C: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | ||
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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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NPC2 | - | - |
GRCh38 GRCh37 |
257 | 285 |
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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000009001.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2020 | RCV001193596.2 |
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
(Mar 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C2
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018352.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001236045.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu118*) in the NPC2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu118*) in the NPC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC2 are known to be pathogenic (PMID: 25145893). This variant is present in population databases (rs80358266, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type C (PMID: 11567215, 25772320, 28808920). ClinVar contains an entry for this variant (Variation ID: 8480). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C2
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000797205.1
First in ClinVar: Aug 29, 2016 Last updated: Aug 29, 2016 |
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Pathogenic
(Dec 04, 2020)
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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: SCV001362526.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 09, 2021 |
Comment:
Variant summary: NPC2 c.352G>T (p.Glu118X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: NPC2 c.352G>T (p.Glu118X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 251482 control chromosomes (gnomAD). c.352G>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (e.g. Millat_2001, Topcu_2017). 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. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 01, 2001)
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no assertion criteria provided
Method: literature only
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NIEMANN-PICK DISEASE, TYPE C2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029215.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 29, 2016 |
Comment on evidence:
In a patient with NPC2 (607625), Millat et al. (2001) found homozygosity for a G-to-T transversion at nucleotide 352 of the HE1 gene, resulting in … (more)
In a patient with NPC2 (607625), Millat et al. (2001) found homozygosity for a G-to-T transversion at nucleotide 352 of the HE1 gene, resulting in a glu118-to-ter (E118X) amino acid change. The patient, who died at 7 months of age, had severe interstitial pneumonia, hepatosplenomegaly, and respiratory failure at 3 months of age. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Niemann-Pick disease type C2
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001464115.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Niemann-Pick disease, type C2
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000041173.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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Niemann-Pick Disease Type C. | Adam MP | - | 2020 | PMID: 20301473 |
Prospective Turkish Cohort Study to Investigate the Frequency of Niemann-Pick Disease Type C Mutations in Consanguineous Families with at Least One Homozygous Family Member. | Topçu M | Molecular diagnosis & therapy | 2017 | PMID: 28808920 |
Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype. | Reunert J | JIMD reports | 2015 | PMID: 25772320 |
Genetic and laboratory diagnostic approach in Niemann Pick disease type C. | McKay Bounford K | Journal of neurology | 2014 | PMID: 25145893 |
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 disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. | Millat G | American journal of human genetics | 2001 | PMID: 11567215 |
Text-mined citations for rs80358266 ...
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.