ClinVar Genomic variation as it relates to human health
NM_000237.3(LPL):c.662T>C (p.Ile221Thr)
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(5); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000237.3(LPL):c.662T>C (p.Ile221Thr)
Variation ID: 1529 Accession: VCV000001529.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8p21.3 8: 19954240 (GRCh38) [ NCBI UCSC ] 8: 19811751 (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 Dec 6, 2016 May 1, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000237.3(LPL):c.662T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000237.3:c.662T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000228.1:p.Ile221Thr missense NC_000008.11:g.19954240T>C NC_000008.10:g.19811751T>C NG_008855.2:g.57524T>C LRG_1298:g.57524T>C LRG_1298t1:c.662T>C LRG_1298p1:p.Ile221Thr P06858:p.Ile221Thr - Protein change
- I221T
- Other names
- I194T
- Canonical SPDI
- NC_000008.11:19954239:T:C
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
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
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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
Help
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 |
750 | 837 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2024 | RCV000001593.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 4, 2022 | RCV001248903.6 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV001388969.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 21, 2023 | RCV003298025.2 |
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
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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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Likely pathogenic
(Dec 22, 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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Genetic Services Laboratory, University of Chicago
Accession: SCV002069631.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the LPL gene demonstrated a sequence change, c.662T>C, in exon 5 that results in an amino acid change, p.Ile221Thr. This sequence … (more)
DNA sequence analysis of the LPL gene demonstrated a sequence change, c.662T>C, in exon 5 that results in an amino acid change, p.Ile221Thr. This sequence change has been described in the gnomAD database with a low overall population frequency of 0.002% and a frequency of 0.005% in east Asian sub group (dbSNP rs118204061). This sequence change has been described in individuals with hypertriglyceridemia in the heterozygous state (PMIDs: 21159338, 27055971, 17717288), and in individuals and family with lipoprotein ligase deficiency in the homozygous and compound heterozygous states (PMIDs: 1674945, 22095987, 16972177). The p.Ile221Thr change affects a highly conserved amino acid residue located in a domain of the lipoprotein lipase (LPL) that is known to be functional. Functional study shows p.Ile221Thr disrupts the enzyme activity of LPL (PMID: 1674945). Collectively these evidences indicate that the p.Ile221Thr variant is pathogenic. (less)
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Likely pathogenic
(Apr 21, 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: SCV003997136.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The p.I221T variant (also known as c.662T>C), located in coding exon 5 of the LPL gene, results from a T to C substitution at nucleotide … (more)
The p.I221T variant (also known as c.662T>C), located in coding exon 5 of the LPL gene, results from a T to C substitution at nucleotide position 662. The isoleucine at codon 221 is replaced by threonine, an amino acid with similar properties. This alteration has been reported as compound heterozygous with known pathogenic mutations in LPL and as homozygous in individuals with familial chylomicronemia syndrome (Dichek HL et al. J Biol Chem, 1991 Jan;266:473-7; Henderson HE et al. J Clin Invest, 1991 Jun;87:2005-11; Reina M et al. J Lipid Res, 1992 Dec;33:1823-32; Nierman MC et al. J Inherit Metab Dis, 2006 Oct;29:686; Ooi EM et al. Arterioscler Thromb Vasc Biol, 2012 Feb;32:459-66; Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86). Additionally, this alteration has been reported as heterozygous in individuals with hypertriglyceridemia (Rodrigues R et al. J Clin Lipidol, 2016 Dec;10:394-409; Wang J et al. Arterioscler Thromb Vasc Biol, 2007 Nov;27:2450-5; Evans D et al. Atherosclerosis, 2011 Feb;214:386-90; Tada H et al. Clin Chim Acta, 2019 Jan;488:31-39). In vitro studies showed this alteration impacts protein function (Fojo SS et al. Eur J Epidemiol, 1992 May;8 Suppl 1:59-63; Peterson J et al. J Lipid Res, 2002 Mar;43:398-406). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipoproteinemia, type I
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000472756.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
Across nine studies, the LPL c.662T>C (p.Ile221Thr) missense variant, which is also referred to as p.Ile194Thr, was identified in 18 subjects with familial lipoprotein lipase … (more)
Across nine studies, the LPL c.662T>C (p.Ile221Thr) missense variant, which is also referred to as p.Ile194Thr, was identified in 18 subjects with familial lipoprotein lipase deficiency or severe hypertriglyceridemia, including four homozygotes, six compound heterozygotes, and eight heterozygotes in whom a second variant was not identified, and in a heterozygous state in at least two unaffected family members of patients (Henderson et al. 1991; Dichek et al. 1991; Santer et al. 2005; Nierman et al. 2006; Wang et al. 2007; Ooi et al. 2011; Rabacchi et al. 2015; Rodrigues et al. 2016; Tani et al. 2016). The variant was absent from 522 total control individuals in these studies. The variant is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, but this is based on only one allele in a region of good sequencing coverage so the variant is presumed to be rare in the general population. Functional studies demonstrated that despite finding the variant protein in the culture medium, the variant protein had virtually no lipolytic activity. Further, the amount of intracellular variant LPL protein was found to be higher than wildtype and it is suggested that the variant protein may not be secreted appropriately (Henderson et al. 1991). These results were confirmed in studies by Dichek et al. (1991) and Fojo et al. (1992). Based on the collective evidence, the p.Ile221Thr variant is classified as pathogenic for familial lipoprotein lipase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Hyperlipidemia, familial combined, LPL related
(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: SCV001422591.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Ile221Thr variant in LPL has been reported in at least 3 individuals (including South African, German, European origin) with familial combined hyperlipidemia, segregated with … (more)
The p.Ile221Thr variant in LPL has been reported in at least 3 individuals (including South African, German, European origin) with familial combined hyperlipidemia, segregated with disease in 2 affected relatives from 1 family (PMID: 21159338, 17717288, 1674945), and has been identified in 0.005% (1/19954) of East Asian, 0.003% (3/129174) of European (non-Finnish), and 0.003% (1/35440) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs118204061). This variant has also been reported in ClinVar as pathogenic (Variation ID: 1529). In vitro functional studies provide some evidence that the p.Ile221Thr variant may impact protein function (PMID: 1505655, 1674945, 11893776). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Three affected individuals with this variant have an alternative molecular basis for familial combined hyperlipidemia, suggesting that this variant may not be pathogenic (PMID: 16972177). In summary, the clinical significance of the p.Ile221Thr variant is uncertain. ACMG/AMP Criteria applied: PS4_supporting, PP3, BP5 (Richards 2015). (less)
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipidemia, familial combined, LPL related
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517576.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Apr 08, 2023)
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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: SCV003918741.1
First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023 |
Comment:
Published functional studies demonstrate that I221T results in defective LPL protein and inactive enzyme (Dichek et al., 1991; Henderson et al., 1991; Fojo et al., … (more)
Published functional studies demonstrate that I221T results in defective LPL protein and inactive enzyme (Dichek et al., 1991; Henderson et al., 1991; Fojo et al., 1992; Peterson et al., 2002; Ooi et al., 2012; Wang et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as I194T; This variant is associated with the following publications: (PMID: 17717288, 30389453, 1505655, 15877202, 16972177, 1702428, 27055971, 27573733, 25966443, 1479292, 11893776, 15256764, 31589614, 32041611, 1674945, 35923617, 22095987, 35820489) (less)
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Pathogenic
(Jan 31, 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: SCV001590163.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 221 of the LPL protein (p.Ile221Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 221 of the LPL protein (p.Ile221Thr). This variant is present in population databases (rs118204061, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of chylomicronemia (PMID: 1674945, 1702428, 15877202, 25966443). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Ile194Thr. ClinVar contains an entry for this variant (Variation ID: 1529). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LPL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LPL function (PMID: 1702428). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipoproteinemia, type I
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810202.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(Jun 01, 1991)
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no assertion criteria provided
Method: literature only
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LIPOPROTEIN LIPASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021749.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2017 |
Comment on evidence:
In a 34-year-old white female with hyperchylomicronemia syndrome (238600), Dichek et al. (1991) found compound heterozygosity for 2 amino acid substitutions: a T-to-C transition at … (more)
In a 34-year-old white female with hyperchylomicronemia syndrome (238600), Dichek et al. (1991) found compound heterozygosity for 2 amino acid substitutions: a T-to-C transition at nucleotide 836 resulted in the substitution of threonine for isoleucine-194 (I194T), and a G-to-A transition at base 983 led to the substitution of histidine for arginine-243 (R243H; 609708.0011) and the loss of an HhaI restriction enzyme site. The woman had been screened for hypertriglyceridemia at birth, after an older sib had been found to have deficiency of LPL. Throughout childhood, she had had recurrent episodes of abdominal pain and pancreatitis, together with eruptive xanthomas, lipemia retinalis, and splenomegaly. In 3 unrelated patients, Henderson et al. (1991) found a T-to-C transition at codon 194 in exon 5 of the LPL gene, resulting in a substitution of threonine for isoleucine. The mutation was associated with 2 different DNA haplotypes, consistent with a multicentric origin of the mutation. One of these patients was later found to be a compound heterozygote (609708.0036). (less)
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Pathogenic
(Mar 17, 2020)
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no assertion criteria provided
Method: clinical testing
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Lipoprotein lipase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002083208.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Clinical whole exome sequencing in severe hypertriglyceridemia. | Tada H | Clinica chimica acta; international journal of clinical chemistry | 2019 | PMID: 30389453 |
High-density lipoprotein subpopulation profiles in lipoprotein lipase and hepatic lipase deficiency. | Tani M | Atherosclerosis | 2016 | PMID: 27573733 |
Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency. | Rodrigues R | Journal of clinical lipidology | 2016 | PMID: 27055971 |
Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia. | Rabacchi C | Atherosclerosis | 2015 | PMID: 25966443 |
Apolipoprotein B-100-containing lipoprotein metabolism in subjects with lipoprotein lipase gene mutations. | Ooi EM | Arteriosclerosis, thrombosis, and vascular biology | 2012 | PMID: 22095987 |
Rare variants in the lipoprotein lipase (LPL) gene are common in hypertriglyceridemia but rare in Type III hyperlipidemia. | Evans D | Atherosclerosis | 2011 | PMID: 21159338 |
Severe hypertriglyceridaemia as a result of familial chylomicronaemia: the Cape Town experience. | Pouwels ED | South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde | 2008 | PMID: 18350203 |
Resequencing genomic DNA of patients with severe hypertriglyceridemia (MIM 144650). | Wang J | Arteriosclerosis, thrombosis, and vascular biology | 2007 | PMID: 17717288 |
Lipoprotein lipase gene analyses in one Turkish family and three different Chinese families with severe hypertriglyceridaemia: one novel and several established mutations. | Nierman MC | Journal of inherited metabolic disease | 2006 | PMID: 16972177 |
Hyperchylomicronaemia due to lipoprotein lipase deficiency as a cause of false-positive newborn screening for biotinidase deficiency. | Santer R | Journal of inherited metabolic disease | 2005 | PMID: 15877202 |
Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene. | Peterson J | Journal of lipid research | 2002 | PMID: 11893776 |
The molecular defects in lipoprotein lipase deficient patients. | Fojo SS | European journal of epidemiology | 1992 | PMID: 1505655 |
Molecular basis of familial chylomicronemia: mutations in the lipoprotein lipase and apolipoprotein C-II genes. | Reina M | Journal of lipid research | 1992 | PMID: 1479292 |
Identification of two separate allelic mutations in the lipoprotein lipase gene of a patient with the familial hyperchylomicronemia syndrome. | Dichek HL | The Journal of biological chemistry | 1991 | PMID: 1702428 |
Amino acid substitution (Ile194----Thr) in exon 5 of the lipoprotein lipase gene causes lipoprotein lipase deficiency in three unrelated probands. Support for a multicentric origin. | Henderson HE | The Journal of clinical investigation | 1991 | PMID: 1674945 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8c095f2a-3e13-47f9-a8c1-9fec9cd6c75c | - | - | - | - |
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Text-mined citations for rs118204061 ...
HelpRecord last updated May 01, 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.