rs118204068
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000237.3(LPL):c.829G>A(p.Asp277Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D277D) has been classified as Likely benign.
Frequency
Consequence
NM_000237.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LPL | NM_000237.3 | c.829G>A | p.Asp277Asn | missense_variant | 6/10 | ENST00000650287.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LPL | ENST00000650287.1 | c.829G>A | p.Asp277Asn | missense_variant | 6/10 | NM_000237.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152110Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251314Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135820
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727234
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74296
ClinVar
Submissions by phenotype
Hyperlipoproteinemia, type I Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1992 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 27, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Feb 15, 2019 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Feb 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | 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. - |
Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 12, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at