ClinVar Genomic variation as it relates to human health
NM_000271.5(NPC1):c.2932C>T (p.Arg978Cys)
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.2932C>T (p.Arg978Cys)
Variation ID: 2976 Accession: VCV000002976.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q11.2 18: 21118615 (GRCh37) [ NCBI UCSC ] 18: 23538651 (GRCh38) [ 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 Apr 20, 2024 May 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000271.5:c.2932C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000262.2:p.Arg978Cys missense NC_000018.10:g.23538651G>A NC_000018.9:g.21118615G>A NG_012795.1:g.52967C>T O15118:p.Arg978Cys - Protein change
- R978C
- Other names
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- Canonical SPDI
- NC_000018.10:23538650: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 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 |
2442 | 2493 |
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
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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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 31, 2023 | RCV000003110.17 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 21, 2019 | RCV000413627.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2017 | RCV004017222.1 |
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
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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
(Nov 21, 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: SCV000331826.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Oct 21, 2019)
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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: SCV000490667.2
First in ClinVar: Jan 09, 2017 Last updated: Dec 15, 2018 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals heterozygous for R978C and another pathogenic variant in NPC1 in association with variant Niemann-Pick disease type C biochemical phenotype and highly variable symptoms and age of onset, ranging from neonatal liver disease to gait ataxia and dysarthria at the age of 20 (Sun et al., 2001; Macias-Vidal et al., 2011; Di Leo et al., 2004; Abela et al., 2014; Perez-Poyato et al., 2012); This variant is associated with the following publications: (PMID: 22750297, 11349231, 15459971, 11479732, 26984608, 24035292, 20718790, 23433426, 28332184, 25425405, 31639011, 32138288, 31589614) (less)
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Pathogenic
(Dec 01, 2017)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002069055.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely pathogenic
(Jan 21, 2016)
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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: SCV000485655.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 24, 2022 |
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Pathogenic
(Nov 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848141.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg978Cys variant in NPC1 has been reported in 1 heterozygous individual with Parkinson disease and 9 individuals with the variant form and/or juvenile/adult onset … (more)
The p.Arg978Cys variant in NPC1 has been reported in 1 heterozygous individual with Parkinson disease and 9 individuals with the variant form and/or juvenile/adult onset of Niemann-Pick disease type C (Di Leo 2004, Kluenemann 2013, Macia-Vidal 2011, Perez-Poyato 2012, Riberio 2001, Schicks 2013, Sedel 2016, Stampfer 2013, Sun 2001). All of the 9 individuals also carried another variant in NPC1 in trans, with at least 2 being known disease-causing variants. It also segregated along with another variant in NPC1 in trans in 4 affected relatives from 3 families (Di Leo 2004, Kluenemann 2013). This variant has also been reported in ClinVar (Variation ID 2976). p.Arg978Cys variant has been identified in 1/9848 of Ashkenazi Jewish and 2/111684 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs28942108). Although this variant has been seen in the general population, its frequency is low enough to be consistent with carrier frequency for Niemann-Pick disease type C. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for the variant form of Niemann-Pick disease type C in an autosomal recessive manner. ACMG/AMP Criteria applied: PM2; PM3_VeryStrong; PP1. (less)
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Pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV000807222.2
First in ClinVar: May 30, 2018 Last updated: Dec 11, 2022 |
Comment:
This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a missense variant in a 15-year-old female … (more)
This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a missense variant in a 15-year-old female with Niemann-Pick Type C (less)
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Pathogenic
(May 31, 2023)
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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: SCV000826854.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 2976). This missense change has been observed in individual(s) with Niemann-Pick disease type C (NPC) (PMID: 11349231, 11479732, 15459971, 20718790, 22750297, 23427322, 23433426, 23774949, 26984608; 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. This variant is present in population databases (rs28942108, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 978 of the NPC1 protein (p.Arg978Cys). (less)
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Pathogenic
(Jul 01, 2001)
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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: SCV000023268.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 30, 2024 |
Comment on evidence:
Among 12 unrelated Portuguese patients with type C Niemann-Pick disease (NPC1; 257220), Ribeiro et al. (2001) identified 1 with a 2932C-T change in exon 20 … (more)
Among 12 unrelated Portuguese patients with type C Niemann-Pick disease (NPC1; 257220), Ribeiro et al. (2001) identified 1 with a 2932C-T change in exon 20 of the NPC1 gene, resulting in an arg978-to-cys substitution. The mutation occurred in compound heterozygous state with a 1-bp deletion (T) at nucleotide 3662 in exon 24 (607623.0021). (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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Normalisation of brain spectroscopy findings in Niemann-Pick disease type C patients treated with miglustat. | Sedel F | Journal of neurology | 2016 | PMID: 26984608 |
GESPA: classifying nsSNPs to predict disease association. | Khurana JK | BMC bioinformatics | 2015 | PMID: 26206375 |
Early co-occurrence of a neurologic-psychiatric disease pattern in Niemann-Pick type C disease: a retrospective Swiss cohort study. | Abela L | Orphanet journal of rare diseases | 2014 | PMID: 25425405 |
Characterization of CoQ₁₀ biosynthesis in fibroblasts of patients with primary and secondary CoQ₁₀ deficiency. | Buján N | Journal of inherited metabolic disease | 2014 | PMID: 23774949 |
Parkinsonism syndrome in heterozygotes for Niemann-Pick C1. | Kluenemann HH | Journal of the neurological sciences | 2013 | PMID: 24035292 |
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 is frequent in adult ataxia with cognitive decline and vertical gaze palsy. | Schicks J | Neurology | 2013 | PMID: 23427322 |
Initiation and discontinuation of substrate inhibitor treatment in patients with Niemann-Pick type C disease. | Pérez-Poyato MS | Gene | 2012 | PMID: 22750297 |
Molecular analysis of 30 Niemann-Pick type C patients from Spain. | Macías-Vidal J | Clinical genetics | 2011 | PMID: 20718790 |
Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations. | Ribeiro I | Human genetics | 2001 | PMID: 11479732 |
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 | - | - | - | - |
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Text-mined citations for rs28942108 ...
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.