ClinVar Genomic variation as it relates to human health
NM_000237.3(LPL):c.835C>G (p.Leu279Val)
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.835C>G (p.Leu279Val)
Variation ID: 855588 Accession: VCV000855588.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8p21.3 8: 19955900 (GRCh38) [ NCBI UCSC ] 8: 19813411 (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 Apr 15, 2020 Feb 14, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000237.3:c.835C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000228.1:p.Leu279Val missense NC_000008.11:g.19955900C>G NC_000008.10:g.19813411C>G NG_008855.2:g.59184C>G LRG_1298:g.59184C>G LRG_1298t1:c.835C>G LRG_1298p1:p.Leu279Val - Protein change
- L279V
- Other names
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- Canonical SPDI
- NC_000008.11:19955899:C:G
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00011
Exome Aggregation Consortium (ExAC) 0.00013
- 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 |
740 | 827 |
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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2024 | RCV001060882.5 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 29, 2022 | RCV001806006.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2022 | RCV002505628.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 5, 2023 | RCV003283939.1 |
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
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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
(Dec 18, 2021)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002051224.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: LPL c.835C>G (p.Leu279Val) results in a conservative amino acid change located in the Lipase domain (IPR013818) of the encoded protein sequence. Three of … (more)
Variant summary: LPL c.835C>G (p.Leu279Val) results in a conservative amino acid change located in the Lipase domain (IPR013818) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency (0.00011 vs 0.0034), allowing no conclusion about variant significance. c.835C>G has been reported as a homozygous and compound heterozygous genotype in the literature in multiple individuals affected with Familial Lipoprotein Lipase Deficiency (example, Kao_1999, Chan_2000, Li_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal Lipoprotein lipase enzyme activity in-vitro (example, Kao_1999, Chan_2000). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipoproteinemia, type I
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058751.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LPL related disorder (ClinVar ID: VCV000855588). Functional studies … (more)
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LPL related disorder (ClinVar ID: VCV000855588). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:10619999, PS3_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID:10619999, PM3_M). A different missense change at the same codon (p.Leu279Arg) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000851236, PMID:8077845, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74, PP3_P). A missense variant is a common mechanism associated with Lipoprotein lipase deficiency (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000124, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hyperlipidemia (present) , Hypertriglyceridemia (present)
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Pathogenic
(Feb 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipidemia, familial combined, LPL related
Hyperlipoproteinemia, type I
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811851.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipoproteinemia, type I
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003835915.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Apr 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003956527.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
The c.835C>G (p.L279V) alteration is located in exon 6 (coding exon 6) of the LPL gene. This alteration results from a C to G substitution … (more)
The c.835C>G (p.L279V) alteration is located in exon 6 (coding exon 6) of the LPL gene. This alteration results from a C to G substitution at nucleotide position 835, causing the leucine (L) at amino acid position 279 to be replaced by a valine (V). Based on data from gnomAD, the G allele has an overall frequency of 0.012% (35/282734) total alleles studied. The highest observed frequency was 0.155% (31/19954) of East Asian alleles. This alteration has been reported as compound heterozygous with an additional LPL alteration in individuals with chylomicronemia syndrome, as well as heterozygous in an individual with hypertriglyceridemia (Chang, 2009; Chen, 2014; Khovidhunkit, 2016; Liu, 2016; Jin, 2018; Li, 2018; Poon, 2019; Han, 2020; Hu, 2021; Tong, 2022). This amino acid position is highly conserved in available vertebrate species. In vitro studies showed this alteration impacts lipase activity (Chan, 2000; Han, 2020). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Aug 16, 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: SCV004028140.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Published functional studies demonstrate reduced LPL activity (Kao et al., 1999; Chen et al., 2014; Han et al., 2020); In silico analysis supports that this … (more)
Published functional studies demonstrate reduced LPL activity (Kao et al., 1999; Chen et al., 2014; Han et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L252V); This variant is associated with the following publications: (PMID: 29921298, 30420299, 33694176, 24646025, 10560236, 16460718, 27206937, 31901151, 27055971, 32041611, 26892137, 32190547, 31352695, 26079787, 33217533) (less)
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Pathogenic
(Jan 26, 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: SCV001225599.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 279 of the LPL protein (p.Leu279Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 279 of the LPL protein (p.Leu279Val). This variant is present in population databases (rs371282890, gnomAD 0.2%). This missense change has been observed in individual(s) with chylomicronemia (PMID: 10560236, 10619999). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Leu252Val. ClinVar contains an entry for this variant (Variation ID: 855588). 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 not expected to disrupt LPL protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LPL function (PMID: 10560236, 10619999). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 21, 2017)
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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: SCV002083217.1
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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Vicious cycle of hypertriglyceridaemia and hyperglycaemia in an atypical case of lipoprotein lipase deficiency. | Tong HF | Pathology | 2022 | PMID: 34635320 |
Whole exome sequencing for non-selective pediatric patients with hyperlipidemia. | Hu X | Gene | 2021 | PMID: 33217533 |
Identification and functional characterization of mutations in LPL gene causing severe hypertriglyceridaemia and acute pancreatitis. | Han P | Journal of cellular and molecular medicine | 2020 | PMID: 31901151 |
Management of severe hypertriglyceridemia due to lipoprotein lipase deficiency in children. | Poon SWY | Endocrinology, diabetes & metabolism case reports | 2019 | PMID: 31352695 |
Intensive genetic analysis for Chinese patients with very high triglyceride levels: Relations of mutations to triglyceride levels and acute pancreatitis. | Jin JL | EBioMedicine | 2018 | PMID: 30420299 |
Compound but non-linked heterozygous p.W14X and p.L279 V LPL gene mutations in a Chinese patient with long-term severe hypertriglyceridemia and recurrent acute pancreatitis. | Li X | Lipids in health and disease | 2018 | PMID: 29921298 |
Rare and common variants in LPL and APOA5 in Thai subjects with severe hypertriglyceridemia: A resequencing approach. | Khovidhunkit W | Journal of clinical lipidology | 2016 | PMID: 27206937 |
A Chinese patient with recurrent pancreatitis during pregnancy induced by hypertriglyceridemia associated with compound heterozygosity (Glu242Lys and Leu252VaL) in the lipoprotein lipase gene. | Liu Y | Journal of clinical lipidology | 2016 | PMID: 26892137 |
A novel lipoprotein lipase gene missense mutation in Chinese patients with severe hypertriglyceridemia and pancreatitis. | Chen TZ | Lipids in health and disease | 2014 | PMID: 24646025 |
Lipoprotein lipase mutation S447X associated with pancreatic calcification and steatorrhea in hyperlipidemic pancreatitis. | Chang YT | Journal of clinical gastroenterology | 2009 | PMID: 19034041 |
Compound heterozygosity of Leu252Val and Leu252Arg causing lipoprotein lipase deficiency in a chinese patient with hypertriglyceridemia. | Chan L | European journal of clinical investigation | 2000 | PMID: 10619999 |
Newly identified missense mutation reduces lipoprotein lipase activity in Taiwanese patients with hypertriglyceridemia. | Kao JT | Journal of the Formosan Medical Association = Taiwan yi zhi | 1999 | PMID: 10560236 |
High frequency of mutations in the human lipoprotein lipase gene in pregnancy-induced chylomicronemia: possible association with apolipoprotein E2 isoform. | Ma Y | Journal of lipid research | 1994 | PMID: 8077845 |
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Text-mined citations for rs371282890 ...
HelpRecord last updated Feb 20, 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.