ClinVar Genomic variation as it relates to human health
NM_000237.3(LPL):c.898_1019-1238dup
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_000237.3(LPL):c.898_1019-1238dup
Variation ID: 1765322 Accession: VCV001765322.2
- Type and length
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Duplication, 2,060 bp
- Location
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Cytogenetic: 8p21.3 8: 19955962-19955963 (GRCh38) [ NCBI UCSC ] 8: 19813473-19813474 (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 Nov 29, 2022 May 1, 2024 Oct 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000237.3:c.898_1019-1238dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000008.11:g.19955963_19958022dup NC_000008.10:g.19813474_19815533dup NG_008855.2:g.59247_61306dup LRG_1298:g.59247_61306dup LRG_1298t1:c.898_1019-1238dup - Protein change
- Other names
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- Canonical SPDI
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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.
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- 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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LPL | - | - |
GRCh38 GRCh37 |
775 | 864 |
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 (1) |
criteria provided, single submitter
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Oct 26, 2023 | RCV002376260.2 |
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
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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
(Oct 26, 2023)
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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: SCV002683699.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.898_1019-1238dup duplication includes at least a portion of coding exon 6 through at least a portion of intron 6 in the LPL gene. This … (more)
The c.898_1019-1238dup duplication includes at least a portion of coding exon 6 through at least a portion of intron 6 in the LPL gene. This variant is reported in the literature as resulting from Alu element-mediated recombination, duplicating approximately 2kb of the LPL gene sequence, which is inserted into intron 6 in tandem to the native sequence of intron 6, between the nucleotides located 1239 bases and 1238 bases upstream of coding exon 7 (Devlin RH et al. Am J Hum Genet 1990 Jan;46(1):112-9). Mobile element insertions typically contribute to pathogenicity by either disrupting the coding sequence or inducing aberrant splicing (Belancio VP et al. Semin Cancer Biol, 2010 Aug;20:200-10; Deininger P et al. Genome Biol, 2011 Dec;12:236; van der Klift HM Hum Mutat, 2012 Jul;33(7):1051-5), however, direct evidence is unavailable. The exact functional effect of the duplicated sequence is unknown. This rearrangement has been reported in several lipoprotein lipase (LPL) deficient individuals of European ancestry with extremely high triglyceride levels. One of these, who also carried a deletion on the other LPL allele, had no detectable LPL protein or enzymatic activity; affected members of three unrelated families who also carried the rearrangement in trans with normal second alleles, had detectable LPL protein levels, but the protein they produced was catalytically defective, demonstrating no LPL activity (Langlois S et al. Proc Natl Acad Sci U S A 1989 Feb;86(3):948-52; Devlin RH et al. Am J Hum Genet 1990 Jan;46(1):112-9). While LPL is an autosomal recessive gene, heterozygote carriers of pathogenic alterations without a detected second mutation (in LPL or other genes likely to cause LPL deficiency) have also been reported to demonstrate LPL deficiency to varying degrees, with phenotypic variability ranging from normal lipid values to extremely high triglyceride levels that may be indistinguishable from the levels found in homozygotes (Babirak SP et al. Arteriosclerosis, 1989 ;9(3):326-34; Nevin DN et al. Arterioscler Thromb 1994 Jun;14(6):869-73; Hegele RA et al. Lancet Diabetes Endocrinol 2014 Aug;2(8):655-66; Dron JS et al. J Clin Lipidol, 2019 Oct;13(1):80-88; Okazaki H et al. J Atheroscler Thromb 2021 Sep;28(9):883-904). Experts have suggested this possibly occurs as the result of a large-effect heterozygous variant in combination with accumulations of common or rare small-effect variants in several genes at many loci (Hegele RA et al. Lancet Diabetes Endocrinol 2014 Aug;2(8):655-66), or that it could also involve the presence of secondary, non-genetic factors (Brunzell JD, Deeb SS. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:2789-816). Additionally, this duplication rearrangement has been described as an early founder mutation, though additional details regarding clinical impact are not available (Devlin RH et al. Am J Hum Genet 1990 Jan;46(1):112-9; Martinez J et al. J Mol Biol 2001 May;308(4):587-96). Based on data from gnomAD, the DUP_8_23990 allele, as it is labeled in the gnomAD SVs v2.1 database, has an overall frequency of 0.023% (5/21694) total alleles studied, including one homozygote. The highest observed frequency was 0.066% (5/7624) of European alleles. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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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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Current Diagnosis and Management of Primary Chylomicronemia. | Okazaki H | Journal of atherosclerosis and thrombosis | 2021 | PMID: 33980761 |
Severe hypertriglyceridemia is primarily polygenic. | Dron JS | Journal of clinical lipidology | 2019 | PMID: 30466821 |
The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. | Hegele RA | The lancet. Diabetes & endocrinology | 2014 | PMID: 24731657 |
Human genetic disorders, a phylogenetic perspective. | Martinez J | Journal of molecular biology | 2001 | PMID: 11350162 |
The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity. | Nevin DN | Arteriosclerosis and thrombosis : a journal of vascular biology | 1994 | PMID: 8199176 |
Partial gene duplication involving exon-Alu interchange results in lipoprotein lipase deficiency. | Devlin RH | American journal of human genetics | 1990 | PMID: 2294743 |
Detection and characterization of the heterozygote state for lipoprotein lipase deficiency. | Babirak SP | Arteriosclerosis (Dallas, Tex.) | 1989 | PMID: 2719595 |
A major insertion accounts for a significant proportion of mutations underlying human lipoprotein lipase deficiency. | Langlois S | Proceedings of the National Academy of Sciences of the United States of America | 1989 | PMID: 2536938 |
Text-mined citations for this variant ...
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.