ClinVar Genomic variation as it relates to human health
NM_000271.5(NPC1):c.1351G>A (p.Glu451Lys)
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.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000271.5(NPC1):c.1351G>A (p.Glu451Lys)
Variation ID: 554990 Accession: VCV000554990.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q11.2 18: 23554960 (GRCh38) [ NCBI UCSC ] 18: 21134924 (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 Aug 5, 2018 Jun 17, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000271.5:c.1351G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000262.2:p.Glu451Lys missense NC_000018.10:g.23554960C>T NC_000018.9:g.21134924C>T NG_012795.1:g.36658G>A - Protein change
- E451K
- Other names
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- Canonical SPDI
- NC_000018.10:23554959: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00006
- Links
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 |
2446 | 2502 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000670724.14 | |
Uncertain significance (1) |
no assertion criteria provided
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Dec 1, 2017 | RCV000675577.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 23, 2022 | RCV002282310.1 |
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
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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
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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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Uncertain significance
(Nov 10, 2017)
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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: SCV000795617.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Sep 11, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000915803.1
First in ClinVar: May 24, 2019 Last updated: May 24, 2019 |
Comment:
The NPC1 c.1351G>A (p.Glu451Lys) variant has been reported in a compound heterozygous state with the same second missense variant in seven individuals from two families, … (more)
The NPC1 c.1351G>A (p.Glu451Lys) variant has been reported in a compound heterozygous state with the same second missense variant in seven individuals from two families, a pair of siblings in one family and five siblings in the second family (Tarugi et al. 2002; Romanello et al. 2016). While all individuals were noted to have Niemann-Pick disease (NPCD), four siblings were 'not classified' due to absence of neurological symptoms (Romanello et al. 2016). In addition, the five siblings exhibited a variant biochemical phenotype based on filipin staining and specific types of oxysterols were observed at either below or slightly above the cut-off noted in patients with NPCD (Romanello et al. 2016). The p.Glu451Lys variant was also identified in a heterozygous state in one individual with the early infantile form who also displayed the variant biochemical phenotype; however, in this individual, a second variant was not identified (De Castro-Oros et al. 2017). The p.Glu451Lys variant was absent from 300 control alleles and is reported at a frequency of 0.000305 in the South Asian population of the Exome Aggregation Consortium. Functional studies of the variant have not been conducted, but it results in a nonconservative substitution of a highly conserved amino acid (Tarugi et al. 2002). Based on the collective evidence, the p.Glu451Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for Niemann-Pick disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Uncertain significance
(Jan 17, 2019)
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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:
inherited
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Baylor Genetics
Accession: SCV001524611.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Jan 12, 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: SCV001390377.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 451 of the NPC1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 451 of the NPC1 protein (p.Glu451Lys). This variant is present in population databases (rs781065429, gnomAD 0.03%). This missense change has been observed in individual(s) with Niemann-Pick, Type C (PMID: 26790753). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 554990). 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 not expected to disrupt NPC1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 23, 2022)
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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: SCV002572259.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: NPC1 c.1351G>A (p.Glu451Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: NPC1 c.1351G>A (p.Glu451Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251370 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (4e-05 vs 0.0027), allowing no conclusion about variant significance. c.1351G>A has been reported in the literature in multiple heterozygous and compound heterozygous individuals affected with Niemann-Pick Disease Type C, and has been found to segregate with disease in at least one family (e.g. Tarugi_2022, Romanello_2016, Marques_2016, DeCastro_2017, Benussi_2019). These data indicate that the variant is likely to be associated with disease. It should be noted that Niemann-Pick Disease Type C has a broad clinical presentation and in the literature individuals with the variant predominately present with the variable biochemical phenotype and few neurological symptoms, which can make a definitive diagnosis and variant classification difficult. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (VUS n=4, pathogenic n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Niemann-Pick disease, type C1
Affected status: no
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051892.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(Dec 01, 2017)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000801268.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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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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Clinical and neurophysiological characteristics of heterozygous NPC1 carriers. | Benussi A | JIMD reports | 2019 | PMID: 31497485 |
Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study. | De Castro-Orós I | Journal of translational medicine | 2017 | PMID: 28222799 |
Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection. | Gong X | Cell | 2016 | PMID: 27238017 |
Comprehensive Evaluation of Plasma 7-Ketocholesterol and Cholestan-3β,5α,6β-Triol in an Italian Cohort of Patients Affected by Niemann-Pick Disease due to NPC1 and SMPD1 Mutations. | Romanello M | Clinica chimica acta; international journal of clinical chemistry | 2016 | PMID: 26790753 |
Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease. | Marques AR | PloS one | 2016 | PMID: 26771826 |
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 |
Text-mined citations for rs781065429 ...
HelpRecord last updated Jun 17, 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.