ClinVar Genomic variation as it relates to human health
NM_001371904.1(APOA5):c.289C>T (p.Gln97Ter)
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_001371904.1(APOA5):c.289C>T (p.Gln97Ter)
Variation ID: 381733 Accession: VCV000381733.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.3 11: 116790940 (GRCh38) [ NCBI UCSC ] 11: 116661656 (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 8, 2017 May 1, 2024 Oct 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001371904.1:c.289C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001358833.1:p.Gln97Ter nonsense NM_001166598.2:c.289C>T NP_001160070.1:p.Gln97Ter nonsense NM_052968.4(APOA5):c.289C>T NM_052968.5:c.289C>T NP_443200.2:p.Gln97Ter nonsense NC_000011.10:g.116790940G>A NC_000011.9:g.116661656G>A NG_015894.2:g.6481C>T - Protein change
- Q97*
- Other names
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- Canonical SPDI
- NC_000011.10:116790939:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- loss_of_function_variant Sequence Ontology [SO:0002054]
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
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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APOA5 | - | - |
GRCh38 GRCh37 |
178 | 245 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Oct 22, 2023 | RCV000428946.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 15, 2019 | RCV000768551.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001249015.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 18, 2022 | RCV002289560.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 22, 2019 | RCV002436266.2 |
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
(Apr 15, 2019)
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criteria provided, single submitter
Method: case-control
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Hypertriglyceridemia 1
(Autosomal recessive inheritance)
Affected status: no, yes
Allele origin:
germline
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Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile
Accession: SCV000897993.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
Comment:
Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a … (more)
Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. (less)
Observation 1:
Clinical Features:
Hypertriglyceridemia (present)
Age: 40-49 years
Sex: female
Ethnicity/Population group: AMR
Geographic origin: Chile
Method: The HumanCytoSNP-12 BeadChip is optimized to detect cytogenetic abnormalities most relevant to human disease. Content includes ~300,000 SNPs targeting regions shown to be important for cytogenetic analysis. The result is dense coverage of ~250 disease regions, including subtelomeric regions, pericentromeric regions, and sex chromosomes, commonly screened in cytogenetics labs. Sufficient SNP coverage is provided to determine dosage sensitivity of >800 genes.
Testing laboratory: Spanish National Genotyping Centre (CeGen)
Date variant was reported to submitter: 2011-03-07
Testing laboratory interpretation: not provided
Observation 2:
Clinical Features:
Hypertriglyceridemia (present)
Age: 50-59 years
Sex: female
Ethnicity/Population group: AMR
Geographic origin: Chile
Method: The HumanCytoSNP-12 BeadChip is optimized to detect cytogenetic abnormalities most relevant to human disease. Content includes ~300,000 SNPs targeting regions shown to be important for cytogenetic analysis. The result is dense coverage of ~250 disease regions, including subtelomeric regions, pericentromeric regions, and sex chromosomes, commonly screened in cytogenetics labs. Sufficient SNP coverage is provided to determine dosage sensitivity of >800 genes.
Testing laboratory: Spanish National Genotyping Centre (CeGen)
Date variant was reported to submitter: 2011-03-07
Testing laboratory interpretation: not provided
Observation 3:
Age: 70-79 years
Sex: female
Ethnicity/Population group: AMR
Geographic origin: Chile
Method: The HumanCytoSNP-12 BeadChip is optimized to detect cytogenetic abnormalities most relevant to human disease. Content includes ~300,000 SNPs targeting regions shown to be important for cytogenetic analysis. The result is dense coverage of ~250 disease regions, including subtelomeric regions, pericentromeric regions, and sex chromosomes, commonly screened in cytogenetics labs. Sufficient SNP coverage is provided to determine dosage sensitivity of >800 genes.
Testing laboratory: Spanish National Genotyping Centre (CeGen)
Date variant was reported to submitter: 2011-03-07
Testing laboratory interpretation: not provided
Observation 4:
Age: 70-79 years
Sex: male
Ethnicity/Population group: AMR
Geographic origin: Chile
Method: The HumanCytoSNP-12 BeadChip is optimized to detect cytogenetic abnormalities most relevant to human disease. Content includes ~300,000 SNPs targeting regions shown to be important for cytogenetic analysis. The result is dense coverage of ~250 disease regions, including subtelomeric regions, pericentromeric regions, and sex chromosomes, commonly screened in cytogenetics labs. Sufficient SNP coverage is provided to determine dosage sensitivity of >800 genes.
Testing laboratory: Spanish National Genotyping Centre (CeGen)
Date variant was reported to submitter: 2011-03-07
Testing laboratory interpretation: not provided
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Pathogenic
(Jan 29, 2020)
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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: SCV000521319.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019 |
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 270 amino acids are lost, and other loss-of-function variants have been … (more)
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 270 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and published literature (Stenson et al., 2014); Published functional studies suggest a damaging effect (LPL activity reduced by 90%, mutant protein not detected by Western blot suggesting a null allele, Charrire et al., 2009); This variant is associated with the following publications: (PMID: 24793350, 18324930, 19447388, 23151256, 25487149, 27108409, 28951076, 32041611) (less)
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Hypertriglyceridemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422870.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Gln97Ter variant in APOA5 has been reported in 18 individuals with hypertriglyceridemia, segregated with disease in 6 affected relatives from 2 families (PMID: 21993410, … (more)
The p.Gln97Ter variant in APOA5 has been reported in 18 individuals with hypertriglyceridemia, segregated with disease in 6 affected relatives from 2 families (PMID: 21993410, 23151256, 23307945, 24291057, 18324930, 24793350, 24591733, 27108409, 19447388, 28951076), and has been identified in 0.01647% (4/24288) of African chromosomes, and at lower frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201079485). In vitro functional studies provide some evidence that the p.Gln97Ter variant may impact protein function (PMID: 18324930). However, these types of assays may not accurately represent biological function. This variant has also been reported in ClinVar (VariaitonID: 381733) as pathogenic by GeneDx. This nonsense variant leads to a premature termination codon at position 97. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the APOA5 gene is an established disease mechanism in hypertriglyceridemia. In summary, this variant meets criteria to be classified as pathogenic for hypertriglyceridemia in an autosomal dominant manner based on the expectation that it will cause loss of function, the increased frequency of the variant in affected individuals and relatives, and functional studies. ACMG/AMP Criteria applied: PVS1_strong, PS4_moderate, PP1_moderate, PS3_supporting (Richards 2015). (less)
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Pathogenic
(Jan 17, 2022)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501779.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Feb 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial type 5 hyperlipoproteinemia
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580827.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1_STR, PS4_MOD, PP1_MOD, PS3_SUP, PM2_SUP
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Dec 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial type 5 hyperlipoproteinemia
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003815556.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 22, 2023)
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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: SCV001581533.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln97*) in the APOA5 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Gln97*) in the APOA5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 270 amino acid(s) of the APOA5 protein. This variant is present in population databases (rs201079485, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal dominant and recessive severe hypertriglyceridemia (PMID: 18324930, 19447388, 23151256, 23307945, 24591733). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381733). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002746794.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Q97* pathogenic mutation (also known as c.289C>T), located in coding exon 3 of the APOA5 gene, results from a C to T substitution at … (more)
The p.Q97* pathogenic mutation (also known as c.289C>T), located in coding exon 3 of the APOA5 gene, results from a C to T substitution at nucleotide position 289. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation has been reported in multiple individuals with hypertriglyceridemia, including severely affected homozygote and compound heterozygote (phase unknown) cases, as well as affected heterozygote carriers (Priore Oliva C et al. J. Intern. Med., 2008 Apr;263:450-8; Charrière S et al. Atherosclerosis, 2009 Nov;207:150-6; Dussaillant C et al. BMC Med. Genet., 2012 Nov;13:106; Mendoza-Barberá E et al. J. Lipid Res., 2013 Mar;54:649-61; Hooper AJ et al. Ann. Clin. Biochem., 2014 Jul;51:485-9; Chokshi N et al. J Clin Lipidol Feb;8:287-95; Lamiquiz-Moneo I et al. Lipids Health Dis, 2016 Apr;15:82). Serum LPL activity was shown to be reduced by approximately 50% in two heterozygote cases and greater than 90% in a homozygous individual (Charrière S et al. Atherosclerosis, 2009 Nov;207:150-6). While premature stop codons are typically deleterious in nature, this stop codon occurs at the 3' terminus of APOA5 and is not expected to trigger nonsense-mediated mRNA decay. However, this variant results in the loss of >25% of the protein, including the C-terminal domain which has been implicated in lipid binding, and is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. (less)
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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
Help
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
Help
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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loss_of_function_variant
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Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile
Accession: SCV000897993.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
Frequency of rare mutations and common genetic variations in severe hypertriglyceridemia in the general population of Spain. | Lamiquiz-Moneo I | Lipids in health and disease | 2016 | PMID: 27108409 |
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
Genotype-phenotype relationships in patients with type I hyperlipoproteinemia. | Chokshi N | Journal of clinical lipidology | 2014 | PMID: 24793350 |
Clinical features and genetic analysis of three patients with severe hypertriglyceridaemia. | Hooper AJ | Annals of clinical biochemistry | 2014 | PMID: 24591733 |
Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia. | Mendoza-Barberá E | Journal of lipid research | 2013 | PMID: 23307945 |
APOA5 Q97X mutation identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family. | Dussaillant C | BMC medical genetics | 2012 | PMID: 23151256 |
Modulation of phenotypic expression of APOA5 Q97X and L242P mutations. | Charrière S | Atherosclerosis | 2009 | PMID: 19447388 |
Hypertriglyceridaemia and low plasma HDL in a patient with apolipoprotein A-V deficiency due to a novel mutation in the APOA5 gene. | Priore Oliva C | Journal of internal medicine | 2008 | PMID: 18324930 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/13f74dad-8776-434f-aedb-a266b5d9930c | - | - | - | - |
Text-mined citations for rs201079485 ...
HelpRecord last updated May 08, 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.