ClinVar Genomic variation as it relates to human health
NM_000040.3(APOC3):c.55C>T (p.Arg19Ter)
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); Uncertain significance(1); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000040.3(APOC3):c.55C>T (p.Arg19Ter)
Variation ID: 17904 Accession: VCV000017904.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.3 11: 116830637 (GRCh38) [ NCBI UCSC ] 11: 116701353 (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 Jul 7, 2014 Apr 6, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000040.3:c.55C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000031.1:p.Arg19Ter nonsense NC_000011.10:g.116830637C>T NC_000011.9:g.116701353C>T NG_008949.1:g.5730C>T - Protein change
- R19*
- Other names
- APOC3, ARG19TER (rs76353203)
- Canonical SPDI
- NC_000011.10:116830636:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- variation affecting protein Variation Ontology [VariO:0002]
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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) 0.00050
Trans-Omics for Precision Medicine (TOPMed) 0.00064
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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APOC3 | - | - |
GRCh38 GRCh37 |
60 | 91 |
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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Uncertain significance (3) |
criteria provided, single submitter
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Mar 29, 2024 | RCV000019493.41 | |
protective (1) |
no assertion criteria provided
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Jun 18, 2014 | RCV000128448.10 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 15, 2024 | RCV000419477.17 | |
Likely benign (1) |
criteria provided, single submitter
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Jul 13, 2020 | RCV001251306.9 |
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
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
(Jun 12, 2015)
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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: SCV000517425.3
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Carriers of the R19X variant in the APOC3 gene have been reported to have increased high-densitylipoprotein levels and decreased triglyceride levels, as compared to non-carriers. … (more)
Carriers of the R19X variant in the APOC3 gene have been reported to have increased high-densitylipoprotein levels and decreased triglyceride levels, as compared to non-carriers. In turn, it has beensuggested that this reduces the risk for heart disease (Crawford et al., 2014; Crosby et al., 2014; Jorgensenet al., 2014). This variant is predicted to cause loss of normal protein function either through proteintruncation or nonsense-mediated mRNA decay. The R19X variant was not observed at any significantfrequency in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. We interpretR19X as a pathogenic variant. (less)
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Likely benign
(Jul 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001426852.1
First in ClinVar: Aug 10, 2020 Last updated: Aug 10, 2020 |
Comment:
Variant summary: APOC3 c.55C>T (p.Arg19X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: APOC3 c.55C>T (p.Arg19X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00066 in 251004 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 33 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOC3 causing Early Onset Coronary Artery Disease phenotype (2e-05), suggesting that the variant is not associated with Early Onset Coronary Artery Disease. In one case-control study, this variant was shown to have protective effect against Early Onset Coronary Artery Disease (Crosby_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Apolipoprotein c-III deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805768.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Likely benign
(Jan 15, 2024)
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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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Invitae
Accession: SCV001637300.4
First in ClinVar: May 23, 2021 Last updated: Feb 20, 2024 |
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Pathogenic
(Jul 03, 2014)
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no assertion criteria provided
Method: literature only
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APOLIPOPROTEIN C-III DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039790.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 28, 2018 |
Comment on evidence:
Pollin et al. (2008) found that 5% of the Lancaster Amish are heterozygous carriers of a null mutation in exon 2 of the APOC3 gene … (more)
Pollin et al. (2008) found that 5% of the Lancaster Amish are heterozygous carriers of a null mutation in exon 2 of the APOC3 gene consisting of a C-to-T transition at nucleotide 55, resulting in an arg19-to-ter (R19X) substitution. As the mutation occurs in the signal peptide of the protein, a complete lack of production of apoC-III from alleles carrying the mutation was predicted. Carriers had half the amount of apoC-III present in noncarriers. Mutation carriers compared with noncarriers had lower fasting and postprandial serum triglycerides, higher levels of HDL cholesterol, and lower levels of LDL cholesterol. Subclinical atherosclerosis, as measured by coronary artery calcification, was less common in carriers than noncarriers, which suggested that lifelong deficiency of apoC-III (614028) has a cardioprotective effect. By sequencing the protein-coding regions of 18,666 genes in 3,734 individuals of European or African ancestry to search for genes associated with plasma triglyceride levels, the TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute (2014) identified 2 carriers of the R19X mutation in the APOC3 gene. Their mean triglyceride level was 45.5 mg/dl, with a mean HDL cholesterol level of 56.8 mg/dl and mean LDL cholesterol level of 152.5 mg/dl. Among 75,725 study participants, Jorgensen et al. (2014) identified 33 heterozygotes for the R19X mutation and found that their mean triglyceride levels were 48% lower than those of noncarriers (p less than 0.001). Among the 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), Saleheen et al. (2017) identified 4 participants homozygous for the APOC3 R19X mutation. When compared with noncarriers, these homozygotes displayed near-absent plasma apoC-III protein (-88.9%; p = 5 x 10(-23)), lower plasma triglyceride concentrations (-59.6%; p = 7 x 10(-4)), higher HDL cholesterol (+26.9 mg/dl; p = 3 x 10(-8)), and similar levels of LDL cholesterol (p = 0.14). Saleheen et al. (2017) recontacted 1 homozygous R19X proband, his wife, and 27 of his first-degree relatives for genotyping and physiologic investigation. They found that proband's wife was also homozygous for the R19X mutation, leading to all 9 children being obligate homozygotes. In this family, they challenged all the homozygotes and noncarriers with a 50g/m(2) oral fat load followed by serial blood testing for 6 hours. The homozygotes had significantly lower postprandial triglyceride excursions (triglyceride area under the curve 468.3 mg/dl over 6 hours versus 1,267.7 mg/dl over 6 hours; p = 1 x 10(-4)). These data showed that complete lack of APOC3 markedly improved clearance of plasma triglycerides after a fatty meal, and were consistent with and extended earlier reports of diminished postprandial lipemia in APOC3 predicted loss-of-function heterozygotes. (less)
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protective
(Jun 18, 2014)
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no assertion criteria provided
Method: literature only
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Coronary heart disease
Affected status: yes
Allele origin:
germline
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000172130.1
First in ClinVar: Jul 07, 2014 Last updated: Jul 07, 2014 |
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Pathogenic
(Mar 03, 2017)
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no assertion criteria provided
Method: case-control
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Apolipoprotein c-III deficiency
(Genetic anticipation)
Affected status: not applicable
Allele origin:
not applicable
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Falavarjan Branch, Islamic Azad University, , and Biochemistry Lab(Mahdieh Medical Diagnostic Center)
Accession: SCV000555657.1
First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018 |
Comment:
We interpret R19X as a pathogenic variant. Mutation carriers compared with noncarriers had lower fasting and postprandial serum triglycerides, higher levels of HDL cholesterol, and … (more)
We interpret R19X as a pathogenic variant. Mutation carriers compared with noncarriers had lower fasting and postprandial serum triglycerides, higher levels of HDL cholesterol, and lower levels of LDL cholesterol. Subclinical atherosclerosis, as measured by coronary artery calcification, was less common in carriers than noncarriers, which suggested that lifelong deficiency of apoC-III has a cardioprotective effect. (less)
Comment on evidence:
Summarized in comments on clinical significance.
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein
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Falavarjan Branch, Islamic Azad University, , and Biochemistry Lab(Mahdieh Medical Diagnostic Center)
Accession: SCV000555657.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. | Saleheen D | Nature | 2017 | PMID: 28406212 |
Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. | Jørgensen AB | The New England journal of medicine | 2014 | PMID: 24941082 |
Loss-of-function mutations in APOC3, triglycerides, and coronary disease. | TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute | The New England journal of medicine | 2014 | PMID: 24941081 |
A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. | Pollin TI | Science (New York, N.Y.) | 2008 | PMID: 19074352 |
Text-mined citations for rs76353203 ...
HelpRecord last updated May 27, 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.