ClinVar Genomic variation as it relates to human health
NM_000041.4(APOE):c.487C>T (p.Arg163Cys)
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.
Uncertain significance(1); Benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000041.4(APOE):c.487C>T (p.Arg163Cys)
Variation ID: 17851 Accession: VCV000017851.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.32 19: 44908783 (GRCh38) [ NCBI UCSC ] 19: 45412040 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 24, 2018 Oct 8, 2024 Feb 15, 2021 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000041.4:c.487C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000032.1:p.Arg163Cys missense NM_001302688.2:c.565C>T NP_001289617.1:p.Arg189Cys missense NM_001302689.2:c.487C>T NP_001289618.1:p.Arg163Cys missense NM_001302690.2:c.487C>T NP_001289619.1:p.Arg163Cys missense NM_001302691.2:c.487C>T NP_001289620.1:p.Arg163Cys missense NC_000019.10:g.44908783C>T NC_000019.9:g.45412040C>T NG_007084.2:g.8002C>T P02649:p.Arg163Cys - Protein change
- R163C, R189C
- Other names
-
R145C
- Canonical SPDI
- NC_000019.10:44908782:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00739 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00142
Exome Aggregation Consortium (ExAC) 0.00264
The Genome Aggregation Database (gnomAD) 0.00701
1000 Genomes Project 30x 0.00718
1000 Genomes Project 0.00739
Trans-Omics for Precision Medicine (TOPMed) 0.00785
- Links
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
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. |
|||
APOE | - | - |
GRCh38 GRCh37 |
189 | 208 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
|
Jan 6, 2020 | RCV000019432.41 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Nov 14, 2020 | RCV000884152.18 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 15, 2021 | RCV001777143.12 | |
Benign (1) |
criteria provided, single submitter
|
Sep 6, 2019 | RCV002326680.9 | |
APOE-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
Aug 5, 2023 | RCV003924846.2 |
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. |
|
---|---|---|---|---|---|
Benign
(Dec 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001027508.2
First in ClinVar: Dec 17, 2019 Last updated: May 04, 2020 |
|
|
Benign
(Oct 28, 2020)
|
criteria provided, single submitter
Method: research
|
not specified
Affected status: unknown
Allele origin:
germline
|
H3Africa Consortium
Study: H3Africa
Accession: SCV002014648.1 First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021 |
Comment:
While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.069, its frequency in African populations is >5%. This suggests that previous classifications of … (more)
While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.069, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. (less)
|
|
Benign
(Feb 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002065969.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
Benign
(Jul 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001836588.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 24239320, 26377243, 3243553, 22069485, 20981092, 11500500, 24507774)
|
|
Uncertain significance
(Nov 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503532.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
Benign
(Sep 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002633850.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
Pathogenic
(Nov 01, 1988)
|
no assertion criteria provided
Method: literature only
|
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039721.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 24, 2018 |
Comment on evidence:
This variant was described by Rall et al. (1982) and Emi et al. (1988). Rall et al. (1982) demonstrated heterogeneity in type III hyperlipoproteinemia (617347). … (more)
This variant was described by Rall et al. (1982) and Emi et al. (1988). Rall et al. (1982) demonstrated heterogeneity in type III hyperlipoproteinemia (617347). They studied 3 subjects who were phenotypically homozygous for apoE2 but showed considerable differences in the binding activity to the fibroblast receptor. The subject with the poorest binding apoE2 was genotypically homozygous for an apoE allele (epsilon 2); cysteine was found at sites A and B. The subject with the most actively binding apoE2 was genotypically homozygous for an apoE allele (epsilon 2*); cysteine was found at site A and at a new site, site C, residue 145, which in apoE2 has arginine. Epsilon 2*, furthermore, specifies a protein with arginine at site B (residue 158). The third subject, whose apoE2 displayed binding activity intermediate between the activities of the other 2, was genotypically heterozygous, having 1 epsilon 2 allele and 1 epsilon 2* allele. (less)
|
|
Likely benign
(Aug 05, 2023)
|
no assertion criteria provided
Method: clinical testing
|
APOE-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004742648.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
Likely pathogenic
(Jan 06, 2020)
|
no assertion criteria provided
Method: curation
|
Familial type 3 hyperlipoproteinemia
Affected status: unknown
Allele origin:
germline
|
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142489.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
NM_000041.2:c.487C>T in the APOE gene has an allele frequency of 0.021 in African subpopulation in the gnomAD database. The p.Arg163Cys (NM_000041.2:c.487C>T) variant has been reported … (more)
NM_000041.2:c.487C>T in the APOE gene has an allele frequency of 0.021 in African subpopulation in the gnomAD database. The p.Arg163Cys (NM_000041.2:c.487C>T) variant has been reported to be associated with type III hyperlipoproteinemia (PMID: 25502880; 26802169). In vitro functional studies suggest that the p.Arg163Cys variant may affect protein function (PMID: 26802169). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PP4; PP3. (less)
|
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 |
---|---|---|---|---|
Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. | Wintjens R | Journal of lipid research | 2016 | PMID: 26802169 |
Genome- and exome-wide association study of serum lipoprotein (a) in the Jackson Heart Study. | Li J | Journal of human genetics | 2015 | PMID: 26377243 |
Comprehensive evaluation of the association of APOE genetic variation with plasma lipoprotein traits in U.S. whites and African blacks. | Radwan ZH | PloS one | 2014 | PMID: 25502880 |
Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. | Peloso GM | American journal of human genetics | 2014 | PMID: 24507774 |
Prevalence of the apolipoprotein E Arg145Cys dyslipidemia at-risk polymorphism in African-derived populations. | Abou Ziki MD | The American journal of cardiology | 2014 | PMID: 24239320 |
Biophysical analysis of apolipoprotein E3 variants linked with development of type III hyperlipoproteinemia. | Georgiadou D | PloS one | 2011 | PMID: 22069485 |
A map of human genome variation from population-scale sequencing. | 1000 Genomes Project Consortium | Nature | 2010 | PMID: 20981092 |
Tuberous xanthomas associated with olanzapine therapy and hypertriglyceridemia in the setting of a rare apolipoprotein E mutation. | Sinnott BP | Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists | 2006 | PMID: 16690468 |
New insights into the heparan sulfate proteoglycan-binding activity of apolipoprotein E. | Libeu CP | The Journal of biological chemistry | 2001 | PMID: 11500500 |
The apolipoprotein E2 (Arg145Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance. | de Villiers WJ | Arteriosclerosis, thrombosis, and vascular biology | 1997 | PMID: 9157949 |
Restriction isotyping of apolipoprotein E R145C in type III hyperlipoproteinemia. | Hsia SH | Journal of investigative medicine : the official publication of the American Federation for Clinical Research | 1995 | PMID: 7735921 |
Genotyping and sequence analysis of apolipoprotein E isoforms. | Emi M | Genomics | 1988 | PMID: 3243553 |
Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich lipoproteins in patients with familial dysbetalipoproteinemia. | Stalenhoef AF | The Journal of clinical investigation | 1986 | PMID: 3745433 |
Identical structural and receptor binding defects in apolipoprotein E2 in hypo-, normo-, and hypercholesterolemic dysbetalipoproteinemia. | Rall SC Jr | The Journal of clinical investigation | 1983 | PMID: 6300187 |
click to load more click to collapse |
Text-mined citations for rs769455 ...
HelpRecord last updated Nov 03, 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.