Submissions for variant NM_000237.3(LPL):c.662T>C (p.Ile221Thr)

gnomAD frequency: 0.00004  dbSNP: rs118204061

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000001593	SCV000472756	pathogenic	Hyperlipoproteinemia, type I	2017-04-27	criteria provided, single submitter	clinical testing	Across nine studies, the LPL c.662T>C (p.Ile221Thr) missense variant, which is also referred to as p.Ile194Thr, was identified in 18 subjects with familial lipoprotein lipase deficiency or severe hypertriglyceridemia, including four homozygotes, six compound heterozygotes, and eight heterozygotes in whom a second variant was not identified, and in a heterozygous state in at least two unaffected family members of patients (Henderson et al. 1991; Dichek et al. 1991; Santer et al. 2005; Nierman et al. 2006; Wang et al. 2007; Ooi et al. 2011; Rabacchi et al. 2015; Rodrigues et al. 2016; Tani et al. 2016). The variant was absent from 522 total control individuals in these studies. The variant is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, but this is based on only one allele in a region of good sequencing coverage so the variant is presumed to be rare in the general population. Functional studies demonstrated that despite finding the variant protein in the culture medium, the variant protein had virtually no lipolytic activity. Further, the amount of intracellular variant LPL protein was found to be higher than wildtype and it is suggested that the variant protein may not be secreted appropriately (Henderson et al. 1991). These results were confirmed in studies by Dichek et al. (1991) and Fojo et al. (1992). Based on the collective evidence, the p.Ile221Thr variant is classified as pathogenic for familial lipoprotein lipase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248903	SCV001422591	uncertain significance	Hyperlipidemia, familial combined, LPL related	2020-01-22	criteria provided, single submitter	curation	The p.Ile221Thr variant in LPL has been reported in at least 3 individuals (including South African, German, European origin) with familial combined hyperlipidemia, segregated with disease in 2 affected relatives from 1 family (PMID: 21159338, 17717288, 1674945), and has been identified in 0.005% (1/19954) of East Asian, 0.003% (3/129174) of European (non-Finnish), and 0.003% (1/35440) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs118204061). This variant has also been reported in ClinVar as pathogenic (Variation ID: 1529). In vitro functional studies provide some evidence that the p.Ile221Thr variant may impact protein function (PMID: 1505655, 1674945, 11893776). 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. Three affected individuals with this variant have an alternative molecular basis for familial combined hyperlipidemia, suggesting that this variant may not be pathogenic (PMID: 16972177). In summary, the clinical significance of the p.Ile221Thr variant is uncertain. ACMG/AMP Criteria applied: PS4_supporting, PP3, BP5 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388969	SCV001590163	pathogenic	not provided	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 221 of the LPL protein (p.Ile221Thr). This variant is present in population databases (rs118204061, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of chylomicronemia (PMID: 1674945, 1702428, 15877202, 25966443). 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 p.Ile194Thr. ClinVar contains an entry for this variant (Variation ID: 1529). 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) indicates that this missense variant is expected to disrupt LPL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LPL function (PMID: 1702428). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001388969	SCV002069631	likely pathogenic	not provided	2020-12-22	criteria provided, single submitter	clinical testing	DNA sequence analysis of the LPL gene demonstrated a sequence change, c.662T>C, in exon 5 that results in an amino acid change, p.Ile221Thr. This sequence change has been described in the gnomAD database with a low overall population frequency of 0.002% and a frequency of 0.005% in east Asian sub group (dbSNP rs118204061). This sequence change has been described in individuals with hypertriglyceridemia in the heterozygous state (PMIDs: 21159338, 27055971, 17717288), and in individuals and family with lipoprotein ligase deficiency in the homozygous and compound heterozygous states (PMIDs: 1674945, 22095987, 16972177). The p.Ile221Thr change affects a highly conserved amino acid residue located in a domain of the lipoprotein lipase (LPL) that is known to be functional. Functional study shows p.Ile221Thr disrupts the enzyme activity of LPL (PMID: 1674945). Collectively these evidences indicate that the p.Ile221Thr variant is pathogenic.
Mendelics	RCV001248903	SCV002517576	pathogenic	Hyperlipidemia, familial combined, LPL related	2022-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001388969	SCV003918741	pathogenic	not provided	2023-04-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that I221T results in defective LPL protein and inactive enzyme (Dichek et al., 1991; Henderson et al., 1991; Fojo et al., 1992; Peterson et al., 2002; Ooi et al., 2012; Wang et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as I194T; This variant is associated with the following publications: (PMID: 17717288, 30389453, 1505655, 15877202, 16972177, 1702428, 27055971, 27573733, 25966443, 1479292, 11893776, 15256764, 31589614, 32041611, 1674945, 35923617, 22095987, 35820489)
Ambry Genetics	RCV003298025	SCV003997136	likely pathogenic	Cardiovascular phenotype	2023-04-21	criteria provided, single submitter	clinical testing	The p.I221T variant (also known as c.662T>C), located in coding exon 5 of the LPL gene, results from a T to C substitution at nucleotide position 662. The isoleucine at codon 221 is replaced by threonine, an amino acid with similar properties. This alteration has been reported as compound heterozygous with known pathogenic mutations in LPL and as homozygous in individuals with familial chylomicronemia syndrome (Dichek HL et al. J Biol Chem, 1991 Jan;266:473-7; Henderson HE et al. J Clin Invest, 1991 Jun;87:2005-11; Reina M et al. J Lipid Res, 1992 Dec;33:1823-32; Nierman MC et al. J Inherit Metab Dis, 2006 Oct;29:686; Ooi EM et al. Arterioscler Thromb Vasc Biol, 2012 Feb;32:459-66; Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86). Additionally, this alteration has been reported as heterozygous in individuals with hypertriglyceridemia (Rodrigues R et al. J Clin Lipidol, 2016 Dec;10:394-409; Wang J et al. Arterioscler Thromb Vasc Biol, 2007 Nov;27:2450-5; Evans D et al. Atherosclerosis, 2011 Feb;214:386-90; Tada H et al. Clin Chim Acta, 2019 Jan;488:31-39). In vitro studies showed this alteration impacts protein function (Fojo SS et al. Eur J Epidemiol, 1992 May;8 Suppl 1:59-63; Peterson J et al. J Lipid Res, 2002 Mar;43:398-406). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000001593	SCV004810202	pathogenic	Hyperlipoproteinemia, type I	2024-04-04	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001388969	SCV005198682	pathogenic	not provided	2024-01-10	criteria provided, single submitter	clinical testing
OMIM	RCV000001593	SCV000021749	pathogenic	Hyperlipoproteinemia, type I	1991-06-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000001593	SCV002083208	pathogenic	Hyperlipoproteinemia, type I	2020-03-17	no assertion criteria provided	clinical testing