ClinVar Genomic variation as it relates to human health

The LPL c.998G>A (p.Arg333His) variant has been reported in four studies in which it is found in at least three individuals affected with lipoprotein lipase deficiency, including in one in a compound heterozygous state with a second missense variant known to result in complete loss of LPL function and in two in a heterozygous state (Martín-Campos et al. 2014; Rabacchi et al. 2015; Rodrigues et al. 2016; Retterstøl et al. 2017). The p.Arg333His variant was absent from 250 control individuals and is reported at a frequency of 0.00067 in the African population of the Genome Aggregation Database. Expression of the p.Arg333His variant in COS-1 cells revealed that postheparin lipoprotein lipase activity was 6% of wild type levels (Martín-Campos et al. 2014). Based on the evidence, the p.Arg333His variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial lipoprotein lipase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Variant summary: LPL c.998G>A (p.Arg333His) results in a non-conservative amino acid change located in the Lipase domain (IPR013818) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251294 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency (4.8e-05 vs 0.0034), allowing no conclusion about variant significance. c.998G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Lipoprotein Lipase Deficiency (example, Martin-Campos_2014). At least one publication reports experimental evidence evaluating an impact on protein function (Martin-Campos_2014). The most pronounced variant effect results in <10% of normal lipoprotein lipase enzyme activity in vitro. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely pathogenic, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Published functional studies demonstrate a damaging effect with decreased enzyme activity (PMID: 24291057); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27055971, 28606150, 34324844, 25966443, 24291057)

This sequence change replaces arginine with histidine at codon 333 of the LPL protein (p.Arg333His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs144466625, ExAC 0.05%). This variant has been observed in individual(s) with chylomichronemia and/or hypertriglyceridemia (PMID: 24291057, 25966443). ClinVar contains an entry for this variant (Variation ID: 632073). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this variant affects LPL protein function (PMID: 24291057). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.R333H variant (also known as c.998G>A), located in coding exon 6 of the LPL gene, results from a G to A substitution at nucleotide position 998. The arginine at codon 333 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as compound heterozygous with an additional pathogenic alteration in LPL in an individual with familial chylomicronemia syndrome (FCS) (Mart&iacute;n-Campos JM et al. Clin Chim Acta, 2014 Feb;429:61-8). This alteration has also been reported in individuals with severe hypertriglyceridemia with no additional pathogenic alteration in LPL identified (Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86; Retterst&oslash;l K et al. Lipids Health Dis, 2017 Jun;16:115). Additionally, this alteration may impact LPL catalytic activity (Mart&iacute;n-Campos JM et al. Clin Chim Acta, 2014 Feb;429:61-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

PP3, PM2, PM3_supporting, PS3