This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 277 of the LPL protein (p.Asp277Asn). This variant is present in population databases (rs118204068, gnomAD 0.005%). This missense change has been observed in individual(s) with chylomicronemia (PMID: 1639392, 25966443, 29748148, 30150141). 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 Asp250Asn. ClinVar contains an entry for this variant (Variation ID: 1539). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LPL protein function. Experimental studies have shown that this missense change affects LPL function (PMID: 1639392). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000237.3(LPL):c.829G>A (p.Asp277Asn)
Germline
Classification
Help
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.
(7)
Help
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/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000237.3(LPL):c.829G>A (p.Asp277Asn)
Variation ID: 1539 Accession: VCV000001539.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 8p21.3 8: 19955894 (GRCh38) [ NCBI UCSC ] 8: 19813405 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 25, 2014 May 1, 2024 Jan 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000237.3:c.829G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000228.1:p.Asp277Asn missense NC_000008.11:g.19955894G>A NC_000008.10:g.19813405G>A NG_008855.2:g.59178G>A LRG_1298:g.59178G>A LRG_1298t1:c.829G>A LRG_1298p1:p.Asp277Asn P06858:p.Asp277Asn - Protein change
- D277N
- Other names
-
D250N
- Canonical SPDI
- NC_000008.11:19955893:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| LPL | - | - |
GRCh38 GRCh37 |
777 | 866 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Feb 15, 2019 | RCV000001604.7 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 17, 2024 | RCV001059212.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 21, 2020 | RCV002426479.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 12, 2021 | RCV002476909.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperlipoproteinemia, type I
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433297.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
|
|
|
Pathogenic
(Sep 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperlipidemia, familial combined, LPL related
Hyperlipoproteinemia, type I
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002784749.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001223829.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 277 of the LPL protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 277 of the LPL protein (p.Asp277Asn). This variant is present in population databases (rs118204068, gnomAD 0.005%). This missense change has been observed in individual(s) with chylomicronemia (PMID: 1639392, 25966443, 29748148, 30150141). 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 Asp250Asn. ClinVar contains an entry for this variant (Variation ID: 1539). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LPL protein function. Experimental studies have shown that this missense change affects LPL function (PMID: 1639392). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Feb 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502123.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Pathogenic
(Jul 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002679278.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D277N pathogenic mutation (also known as c.829G>A), located in coding exon 6 of the LPL gene, results from a G to A substitution at … (more)
The p.D277N pathogenic mutation (also known as c.829G>A), located in coding exon 6 of the LPL gene, results from a G to A substitution at nucleotide position 829. The aspartic acid at codon 277 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in the homozygous and compound heterozygous states in numerous individuals with familial chylomicronemia syndrome (FCS) (Ishimura-Oka K et al. J. Lipid Res., 1992 May;33:745-54; Wiebusch H et al. Hum. Mutat., 1996;8:381-3; Bijvoet SM et al. Neth J Med, 1996 Nov;49:189-95; Martín-Campos JM et al. Clin. Chim. Acta, 2014 Feb;429:61-8; Ma Y et al. Genomics, 1992 Jul;13:649-53; Rodrigues R et al. J Clin Lipidol Dec;10:394-409; Ariza MJ et al. J Clin Lipidol Aug;12:1482-1492.e3; Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86). In the heterozygous state, this variant has been associated with moderate to severe hypertriglyceridemia (Surendran RP et al. J. Intern. Med., 2012 Aug;272:185-96; Minicocci I et al. Atherosclerosis, 2015 Oct;242:618-24). Functional studies indicate that this alteration results in deficient protein function (Ishimura-Oka K et al. J. Lipid Res., 1992 May;33:745-54; Ma Y et al. Genomics, 1992 Jul;13:649-53; Martín-Campos JM et al. Clin. Chim. Acta, 2014 Feb;429:61-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Jul 01, 1992)
|
no assertion criteria provided
Method: literature only
|
LIPOPROTEIN LIPASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021760.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 25, 2014 |
Comment on evidence:
In a French Canadian patient, Ma et al. (1992) found a G-to-A transition in exon 6 of the LPL gene, resulting in substitution of asparagine … (more)
In a French Canadian patient, Ma et al. (1992) found a G-to-A transition in exon 6 of the LPL gene, resulting in substitution of asparagine for aspartic acid at residue 250 (D250N), as the basis of familial chylomicronemia (238600). Using in vitro site-directed mutagenesis, they confirmed that the mutation caused a catalytically defective LPL protein. The D250N mutation was also found on the same haplotype in an LPL-deficient patient of Dutch ancestry, suggesting a common origin. The mutation altered a TaqI restriction site, thus allowing for rapid screening in patients with LPL deficiency. (less)
|
|
|
Pathogenic
(Oct 27, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Lipoprotein lipase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002083216.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
The p.D277N pathogenic mutation (also known as c.829G>A), located in coding exon 6 of the LPL gene, results from a G to A substitution at nucleotide position 829. The aspartic acid at codon 277 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in the homozygous and compound heterozygous states in numerous individuals with familial chylomicronemia syndrome (FCS) (Ishimura-Oka K et al. J. Lipid Res., 1992 May;33:745-54; Wiebusch H et al. Hum. Mutat., 1996;8:381-3; Bijvoet SM et al. Neth J Med, 1996 Nov;49:189-95; Martín-Campos JM et al. Clin. Chim. Acta, 2014 Feb;429:61-8; Ma Y et al. Genomics, 1992 Jul;13:649-53; Rodrigues R et al. J Clin Lipidol Dec;10:394-409; Ariza MJ et al. J Clin Lipidol Aug;12:1482-1492.e3; Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86). In the heterozygous state, this variant has been associated with moderate to severe hypertriglyceridemia (Surendran RP et al. J. Intern. Med., 2012 Aug;272:185-96; Minicocci I et al. Atherosclerosis, 2015 Oct;242:618-24). Functional studies indicate that this alteration results in deficient protein function (Ishimura-Oka K et al. J. Lipid Res., 1992 May;33:745-54; Ma Y et al. Genomics, 1992 Jul;13:649-53; Martín-Campos JM et al. Clin. Chim. Acta, 2014 Feb;429:61-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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. |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 277 of the LPL protein (p.Asp277Asn). This variant is present in population databases (rs118204068, gnomAD 0.005%). This missense change has been observed in individual(s) with chylomicronemia (PMID: 1639392, 25966443, 29748148, 30150141). 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 Asp250Asn. ClinVar contains an entry for this variant (Variation ID: 1539). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LPL protein function. Experimental studies have shown that this missense change affects LPL function (PMID: 1639392). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.D277N pathogenic mutation (also known as c.829G>A), located in coding exon 6 of the LPL gene, results from a G to A substitution at nucleotide position 829. The aspartic acid at codon 277 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in the homozygous and compound heterozygous states in numerous individuals with familial chylomicronemia syndrome (FCS) (Ishimura-Oka K et al. J. Lipid Res., 1992 May;33:745-54; Wiebusch H et al. Hum. Mutat., 1996;8:381-3; Bijvoet SM et al. Neth J Med, 1996 Nov;49:189-95; Martín-Campos JM et al. Clin. Chim. Acta, 2014 Feb;429:61-8; Ma Y et al. Genomics, 1992 Jul;13:649-53; Rodrigues R et al. J Clin Lipidol Dec;10:394-409; Ariza MJ et al. J Clin Lipidol Aug;12:1482-1492.e3; Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86). In the heterozygous state, this variant has been associated with moderate to severe hypertriglyceridemia (Surendran RP et al. J. Intern. Med., 2012 Aug;272:185-96; Minicocci I et al. Atherosclerosis, 2015 Oct;242:618-24). Functional studies indicate that this alteration results in deficient protein function (Ishimura-Oka K et al. J. Lipid Res., 1992 May;33:745-54; Ma Y et al. Genomics, 1992 Jul;13:649-53; Martín-Campos JM et al. Clin. Chim. Acta, 2014 Feb;429:61-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Molecular basis of the familial chylomicronemia syndrome in patients from the National Dyslipidemia Registry of the Spanish Atherosclerosis Society. | Ariza MJ | Journal of clinical lipidology | 2018 | PMID: 30150141 |
| Clinical and biochemical features of different molecular etiologies of familial chylomicronemia. | Hegele RA | Journal of clinical lipidology | 2018 | PMID: 29748148 |
| Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency. | Rodrigues R | Journal of clinical lipidology | 2016 | PMID: 27055971 |
| Contribution of mutations in low density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) genes to familial combined hyperlipidemia (FCHL): a reappraisal by using a resequencing approach. | Minicocci I | Atherosclerosis | 2015 | PMID: 26342331 |
| Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia. | Rabacchi C | Atherosclerosis | 2015 | PMID: 25966443 |
| Molecular analysis of chylomicronemia in a clinical laboratory setting: diagnosis of 13 cases of lipoprotein lipase deficiency. | Martín-Campos JM | Clinica chimica acta; international journal of clinical chemistry | 2014 | PMID: 24291057 |
| Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. | Surendran RP | Journal of internal medicine | 2012 | PMID: 22239554 |
| Compound heterozygosity for a known and a novel defect in the lipoprotein lipase gene (Asp250-->Asn; Ser251-->Cys) resulting in lipoprotein lipase (LPL) deficiency. | Bijvoet SM | The Netherlands journal of medicine | 1996 | PMID: 8973094 |
| Compound heterozygosity for a known (D250N) and a novel (E410K) missense mutation in the C-terminal domain of lipoprotein lipase causes familial chylomicronemia. | Wiebusch H | Human mutation | 1996 | PMID: 8956048 |
| A missense mutation (Asp250----Asn) in exon 6 of the human lipoprotein lipase gene causes chylomicronemia in patients of different ancestries. | Ma Y | Genomics | 1992 | PMID: 1639392 |
| A missense (Asp250----Asn) mutation in the lipoprotein lipase gene in two unrelated families with familial lipoprotein lipase deficiency. | Ishimura-Oka K | Journal of lipid research | 1992 | PMID: 1619366 |
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Text-mined citations for rs118204068 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.