ClinVar Genomic variation as it relates to human health
NM_000271.5(NPC1):c.1211G>A (p.Arg404Gln)
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.1211G>A (p.Arg404Gln)
Variation ID: 188794 Accession: VCV000188794.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q11.2 18: 23556358 (GRCh38) [ NCBI UCSC ] 18: 21136322 (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 Mar 29, 2015 Feb 14, 2024 Dec 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000271.5:c.1211G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000262.2:p.Arg404Gln missense NC_000018.10:g.23556358C>T NC_000018.9:g.21136322C>T NG_012795.1:g.35260G>A O15118:p.Arg404Gln - Protein change
- R404Q
- Other names
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- Canonical SPDI
- NC_000018.10:23556357:C:T
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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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
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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
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. |
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NPC1 | - | - |
GRCh38 GRCh37 |
2459 | 2516 |
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. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2023 | RCV000169124.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 23, 2021 | RCV000255152.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 1, 2016 | RCV000588149.2 |
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 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C1
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000596047.1
First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
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Pathogenic
(Dec 01, 2016)
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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: SCV000696414.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.1211G>A (p.Arg404Gln) in NPC1 gene is a missense change that alters a highly conserved nucleotide and 4/5 in silico tools predict deleterious … (more)
Variant summary: The c.1211G>A (p.Arg404Gln) in NPC1 gene is a missense change that alters a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. These predictions were also confirmed by functional studies, where very low esterification values were found in fibroblasts of a patient homozygous for R404Q. The variant is present in the large control population dataset of ExAC at a frequency 0.000041 (5/121346 chrs tested), which does not exceed the estimated maximal expected allele frequency of a pathogenic variant (0.0028). The variant was identified in multiple affected individuals with established dx of classical NPC. Lastly, multiple reputable diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic. (less)
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Pathogenic
(Oct 31, 2018)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893491.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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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: SCV001163440.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Sep 23, 2021)
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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: SCV000321923.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Relatively common in affected patients, occurring on 3.1% of NPC1 alleles (Park et al., 2003) Published functional studies demonstrate R404Q significantly decreased binding to NPC2 … (more)
Relatively common in affected patients, occurring on 3.1% of NPC1 alleles (Park et al., 2003) Published functional studies demonstrate R404Q significantly decreased binding to NPC2 compared the wild-type protein (Deffieu et al., 2011) Not observed at a significant frequency in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 32317543, 32222928, 22065762, 26981555, 19744920, 27581084, 12955717, 11349231, 30188717, 11545687, 15465421, 12974729, 10480349, 27307437, 26666848, 11333381) (less)
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Pathogenic
(Dec 21, 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: SCV000956950.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 404 of the NPC1 protein (p.Arg404Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 404 of the NPC1 protein (p.Arg404Gln). This variant is present in population databases (rs139751448, gnomAD 0.009%). This missense change has been observed in individual(s) with Nieman-Pick disease type C (PMID: 11349231, 11545687, 26666848, 27581084; Invitae). 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: 188794). 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%. Experimental studies have shown that this missense change affects NPC1 function (PMID: 22065762). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 23, 2019)
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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:
unknown
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Counsyl
Accession: SCV000220334.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
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Pathogenic
(Feb 08, 2021)
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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: SCV002095214.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Ataxia, dystonia and myoclonus in adult patients with Niemann-Pick type C. | Koens LH | Orphanet journal of rare diseases | 2016 | PMID: 27581084 |
Identification of novel bile acids as biomarkers for the early diagnosis of Niemann-Pick C disease. | Mazzacuva F | FEBS letters | 2016 | PMID: 27139891 |
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 |
Niemann-Pick type C 1 function requires lumenal domain residues that mediate cholesterol-dependent NPC2 binding. | Deffieu MS | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 22065762 |
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 |
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 |
Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C. | Meiner V | Genetics in medicine : official journal of the American College of Medical Genetics | 2001 | PMID: 11545687 |
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 |
Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. | Millat G | American journal of human genetics | 2001 | PMID: 11333381 |
Text-mined citations for rs139751448 ...
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.