Submissions for variant NM_000237.3(LPL):c.644G>A (p.Gly215Glu)

gnomAD frequency: 0.00024  dbSNP: rs118204057

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521241	SCV000617843	pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in association with hyperlipoproteinemia or hypertriglyceridemia (Chokshi et al., 2014; Johansen et al., 2014; Rodrigues et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID# 1522; ClinVar); Functional studies have demonstrated that G215E results in a complete loss of catalytic activity (Hata et al., 1992); This variant is associated with the following publications: (PMID: 28534127, 1619366, 1969408, 12905705, 18922999, 24793350, 24503134, 27055971, 24747307, 22095987, 24493316, 1975597, 1400331, 30150141, 29748148, 30210108, 32472350, 28438574, 29288010, 34426522, 31589614, 32041611, 33303402, 1351946)
Fulgent Genetics, Fulgent Genetics	RCV000763181	SCV000893780	pathogenic	Hyperlipidemia, familial combined, LPL related; Hyperlipoproteinemia, type I	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000521241	SCV000935254	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 215 of the LPL protein (p.Gly215Glu). This variant is present in population databases (rs118204057, gnomAD 0.03%). This missense change has been observed in individuals with lipoprotein lipase deficiency (PMID: 1969408, 22095987, 28438574). This variant is also known as p.Gly188Glu. ClinVar contains an entry for this variant (Variation ID: 1522). 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: 1400331, 1969408, 29288010). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248904	SCV001422593	likely pathogenic	Hyperlipidemia, familial combined, LPL related	2024-08-05	criteria provided, single submitter	curation	The p.Gly215Glu variant in LPL has been reported in >10 individuals with familial combined hyperlipidemia (PMID: 1975597, 1969408, 11334614, 30352774, 36274861, 36476373, 35460704, 22095987), but has been identified in 0.2% (2/912) of Amish chromosomes and other populations at a lesser frequency by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs118204057). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at frequency higher than expected in the general population. In vitro functional studies provide some evidence that the p.Gly215Glu variant may slightly impact protein function (PMID: 1969408, 29288010). 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. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant familial combined hyperlipidemia. ACMG/AMP Criteria applied: PS4_strong, PP3, PS3_supporting (Richards 2015).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001248904	SCV001754801	pathogenic	Hyperlipidemia, familial combined, LPL related	2019-08-29	criteria provided, single submitter	clinical testing	The c.644G>A (p.Gly215Glu) variant (also known as Gly188Glu, rs118204057) in the LPL gene has been reported numerous times in association with autosomal recessive LPL deficiency when present in the homozygous or compound heterozygous state (PMID: 1975597, 29288010, 29748148). It has also been reported in association with significantly elevated triglyceride levels and pancreatitis in the heterozygous state (PMID: 24793350, 2719595, 22239554). This variant is present in 50/282856 alleles in the gnomAD population database. Functional studies show a loss of enzyme activity resulting from this variant (PMID: 1400331). This variant is considered pathogenic.
DASA	RCV000001586	SCV002061296	pathogenic	Hyperlipoproteinemia, type I	2022-01-05	criteria provided, single submitter	clinical testing	The c.644G>A;p.(Gly215Glu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 1522; PMID: 29288010; 22095987; 9401010; 1351946; PMID: 26337181) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 29288010) - PS3_supporting. The variant is present at low allele frequencies population databases (rs118204057– gnomAD 0.002432%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly215Glu) was detected in trans with a pathogenic variant (PMID: 29288010; 22095987; 9401010; 1351946; 26337181) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 26337181) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID: 29288010) - BP2. In summary, the currently available evidence indicates that the variant is pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000521241	SCV002503124	likely pathogenic	not provided	2022-02-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362549	SCV002656807	pathogenic	Cardiovascular phenotype	2023-11-20	criteria provided, single submitter	clinical testing	The p.G215E pathogenic mutation (also known as c.644G>A), located in coding exon 5 of the LPL gene, results from a G to A substitution at nucleotide position 644. The glycine at codon 215 is replaced by glutamic acid, an amino acid with similar properties. This mutation has been reported to be a founder mutation and has been detected in the homozygous and compound heterozygous states in numerous individuals with familial chylomicronemia (FCS) (e.g., Monsalve MV et al. J. Clin. Invest., 1990 Sep;86:728-34; Henderson HE et al. J. Med. Genet., 1992 Feb;29:119-22; Gilbert B et al. Ann. Genet.2011;44:25-32; Hooper AJ et al. Ann. Clin. Biochem., 2014 Jul;51:485-9; Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86; Hegele RA et al. J Clin Lipidol 2018 Apr;12:920-927.e4). In the heterozygous state, this alteration has been associated with hyperlipoproteinemia (Chokshi N et al. J Clin Lipidol 2014 Feb;8:287-95; Johansen CT et al. J. Lipid Res., 2014 Apr;55:765-72; Rodrigues R et al. J Clin Lipidol 2016 Dec;10:394-409). Functional studies indicate that this alteration results in deficient protein function (Emi M et al. J. Biol. Chem., 1990 Apr;265:5910-6; Hata A et al. J. Biol. Chem., 1992 Oct;267:20132-9; Caddeo A et al. Nutr Metab Cardiovasc Dis, 2018 02;28:158-164). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000521241	SCV003823435	pathogenic	not provided	2023-08-25	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000001586	SCV003845191	pathogenic	Hyperlipoproteinemia, type I		criteria provided, single submitter	clinical testing
New York Genome Center	RCV001248904	SCV003925391	pathogenic	Hyperlipidemia, familial combined, LPL related	2022-06-17	criteria provided, single submitter	clinical testing	The c.644G>A p.(Gly215Glu) variant [historically called p.(Gly188Glu) in the literature] has previously been reported in multiple individuals in homozygous or compound heterozygous state with lipoprotein lipase deficiency [PMID: 1975597, 29288010, 29748148, 30210108, 27055971, 1969408, 1351946]. Moreover, the variant co-segregated with the disease in multiple affected family members [PMID:26337181, 1969408]. In the heterozygous sate, this variant has been reported in individuals with elevated triglyceride levels [PMID: 24793350, 2719595, 22239554, 27055971]. The variant has been deposited in ClinVar [ClinVar ID: 1522] as LikelyPathogenic/Pathogenic (6 entries) and Variant of Uncertain Significance (1 entry). The c.644G>A variant is observed in 85 alleles (0.00021 minor allele frequency with0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2). The c.644G>A variant is located in exon 5 of this 10-exon gene and is predicted to replace an evolutionarily conserved glycine amino acid with glutamic acid at codon 215 in the lipase domain of the encoded protein [PMID: 34544385]. In silico predictions are in favor of the damaging effect for the p.(Gly215Glu) variant [REVEL score =0.705]. In vitro functional studies demonstrated reduced catalytic activity and protein function in HEK293T and COS-1 cells carrying c.644G>A variant [PMID: 1400331, 29288010, 1969408]. Based on available evidence this c.644G>A p.(Gly215Glu) variant identified in LPL is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415622	SCV004118140	pathogenic	LPL-related disorder	2023-11-27	criteria provided, single submitter	clinical testing	The LPL c.644G>A variant is predicted to result in the amino acid substitution p.Gly215Glu. This variant (also known as p.Gly188Glu), has been reported in the homozygous or compound heterozygous state in multiple patients with lipoprotein lipase deficiency and familial chylomicronemia syndrome (FCS) (Emi et al. 1990. PubMed ID: 1969408; Monsalve et al. 1990. PubMed ID: 1975597; Ooi et al. 2012. PubMed ID: 22095987; Bordugo et al. 2014. PubMed ID: 24747307; Hegele et al. 2018. PubMed ID: 29748148; Ariza et al. 2018. PubMed ID: 30150141). Heterozygous carriers of this variant are also reported to have a wide range of fasting triglyceride concentrations (Wilson et al. 1990. PubMed ID: 2394828; Hooper et al. 2008. PubMed ID: 18275685; Chokshi et al. 2014. PubMed ID: 24793350; Johansen et al. 2014. PubMed ID: 24503134; Rodrigues et al. 2016. PubMed ID: 27055971). Functional studies also suggest this variant decreases LPL protein activity (Caddeo et al. 2018. PubMed ID: 29288010). This variant is reported in 0.030% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000521241	SCV004226795	pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	PP1_strong, PM3, PS3, PS4_moderate
OMIM	RCV000001586	SCV000021742	pathogenic	Hyperlipoproteinemia, type I	2001-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000001586	SCV001456338	pathogenic	Hyperlipoproteinemia, type I	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000521241	SCV001923354	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000521241	SCV001959948	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV001248904	SCV004101104	pathogenic	Hyperlipidemia, familial combined, LPL related	2023-11-02	no assertion criteria provided	clinical testing