Submissions for variant NM_000237.3(LPL):c.829G>A (p.Asp277Asn)

gnomAD frequency: 0.00001  dbSNP: rs118204068

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059212	SCV001223829	pathogenic	not provided	2024-12-31	criteria provided, single submitter	clinical testing	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). Invitae Evidence 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 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000001604	SCV001433297	pathogenic	Hyperlipoproteinemia, type I	2019-02-15	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001059212	SCV002502123	likely pathogenic	not provided	2022-02-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426479	SCV002679278	pathogenic	Cardiovascular phenotype	2020-07-21	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002476909	SCV002784749	pathogenic	Hyperlipidemia, familial combined, LPL related; Hyperlipoproteinemia, type I	2021-09-12	criteria provided, single submitter	clinical testing
OMIM	RCV000001604	SCV000021760	pathogenic	Hyperlipoproteinemia, type I	1992-07-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000001604	SCV002083216	pathogenic	Hyperlipoproteinemia, type I	2020-10-27	no assertion criteria provided	clinical testing