ClinVar Genomic variation as it relates to human health
NM_000039.3(APOA1):c.388AAG[1] (p.Lys131del)
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(4); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000039.3(APOA1):c.388AAG[1] (p.Lys131del)
Variation ID: 636899 Accession: VCV000636899.10
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 11q23.3 11: 116836219-116836221 (GRCh38) [ NCBI UCSC ] 11: 116706935-116706937 (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 27, 2019 May 1, 2024 Jan 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000039.3:c.388AAG[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000030.1:p.Lys131del inframe deletion NM_000039.1:c.391_393del inframe indel NM_000039.1:c.391_393delAAG inframe indel NM_000039.2:c.391_393del NM_001318017.2:c.388AAG[1] NP_001304946.1:p.Lys131del inframe deletion NM_001318018.2:c.388AAG[1] NP_001304947.1:p.Lys131del inframe deletion NM_001318018.2:c.391_393del inframe deletion NM_001318021.2:c.59_61AGA[1] NP_001304950.1:p.Lys22del inframe indel NR_126362.1:n.105TCT[1] non-coding transcript variant NC_000011.10:g.116836221TCT[1] NC_000011.9:g.116706937TCT[1] NG_012021.1:g.6399AAG[1] LRG_767:g.6399AAG[1] LRG_767t1:c.386_388AGA[1] LRG_767p1:p.Lys131del - Protein change
- K131del, K22del
- Other names
- p.131_131del
- Canonical SPDI
- NC_000011.10:116836218:CTTCTTCT:CTTCT
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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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0.00060 (CTTCT)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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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
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. |
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APOA1 | - | - |
GRCh38 GRCh37 |
101 | 319 | |
APOA1-AS | - | - | GRCh38 | - | 209 |
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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Uncertain significance (2) |
criteria provided, single submitter
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Jan 15, 2024 | RCV000788861.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 1, 2019 | RCV001262205.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 10, 2022 | RCV001824880.1 | |
Likely benign (1) |
criteria provided, single submitter
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Dec 30, 2021 | RCV002370060.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 28, 2020 | RCV001171337.1 |
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
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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Uncertain significance
(May 28, 2020)
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criteria provided, single submitter
Method: research
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Chronic kidney disease
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Cavalleri Lab, Royal College of Surgeons in Ireland
Accession: SCV001328284.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
PM4, BS1
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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial visceral amyloidosis, Ostertag type
Affected status: no
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001439992.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Uncertain significance
(Jan 10, 2022)
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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: SCV002074169.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: APOA1 c.391_393delAAG (p.Lys131del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele … (more)
Variant summary: APOA1 c.391_393delAAG (p.Lys131del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00025 in 251448 control chromosomes. The observed variant frequency is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOA1 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. c.391_393delAAG has been reported in the literature in individuals affected with premature coronary heart disease, low/median HDL-C levels, or dyslipidemia and related metabolic traits (e.g. Tilly-Kiesi_ATVB, Haase_2012, Sadananda_2015, Dron_2020). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Two publications report experimental evidence evaluating an impact on protein function and showed that this variant results in decreased stability, increased propensity to aggregate at physiological pH, a slight increase in cholesteryl ester (Ramella_2012, Toledo_2013). However, it is not clear if these effect will lead to disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic n=1, VUS n=2). Based on the evidence outlined above, the variant was classified as VUS. (less)
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Uncertain significance
(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: SCV002109110.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant, c.391_393del, results in the deletion of 1 amino acid(s) of the APOA1 protein (p.Lys131del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.391_393del, results in the deletion of 1 amino acid(s) of the APOA1 protein (p.Lys131del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs532489785, gnomAD 0.04%). This variant has been observed in individual(s) with amyloidosis or reduced HDL cholesterol and cardiovascular disease (PMID: 7670941, 9464251, 23209431, 24273187, 26255038, 29150341, 30333156). This variant is also known as Lys107del, K107del, Lys107>0, ApoA-I Helsinki, or deltaK107. ClinVar contains an entry for this variant (Variation ID: 636899). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects APOA1 function (PMID: 22952757, 23456478). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Dec 30, 2021)
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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: SCV002624062.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely 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)
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Pathogenic
(Dec 19, 2018)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Not provided
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000928131.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019
Comment:
Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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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 |
Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. | Geller AS | Journal of lipid research | 2018 | PMID: 30333156 |
Increased prevalence of clinical and subclinical atherosclerosis in patients with damaging mutations in ABCA1 or APOA1. | Abdel-Razek O | Journal of clinical lipidology | 2018 | PMID: 29150341 |
Targeted next-generation sequencing to diagnose disorders of HDL cholesterol. | Sadananda SN | Journal of lipid research | 2015 | PMID: 26255038 |
Premature atherosclerosis, extremely low HDL-cholesterol and concurrent defects in APOA1 and ABCA1 genes: a family case report. | Koopal C | International journal of cardiology | 2014 | PMID: 25127959 |
ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C. | Ljunggren S | Proteomics. Clinical applications | 2014 | PMID: 24273187 |
Apolipoprotein A-I Helsinki promotes intracellular acyl-CoA cholesterol acyltransferase (ACAT) protein accumulation. | Toledo JD | Molecular and cellular biochemistry | 2013 | PMID: 23456478 |
Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach. | Haase CL | PLoS genetics | 2012 | PMID: 23209431 |
Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity. | Ramella NA | PloS one | 2012 | PMID: 22952757 |
Extensive intimal apolipoprotein A1-derived amyloid deposits in a patient with an apolipoprotein A1 mutation. | Amarzguioui M | Biochemical and biophysical research communications | 1998 | PMID: 9464251 |
ApoA-IHelsinki (Lys107-->0) associated with reduced HDL cholesterol and LpA-I:A-II deficiency. | Tilly-Kiesi M | Arteriosclerosis, thrombosis, and vascular biology | 1995 | PMID: 7670941 |
Abnormal lecithin:cholesterol acyltransferase activation by a human apolipoprotein A-I variant in which a single lysine residue is deleted. | Rall SC Jr | The Journal of biological chemistry | 1984 | PMID: 6432779 |
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Text-mined citations for rs532489785 ...
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.