ClinVar Genomic variation as it relates to human health

Identified in the heterozygous state in individuals with hypertriglyceridemia, also described as A71T due to use of alternate nomenclature (Chan et al., 2002; Hu et al., 2007; Khovidhunkit et al., 2016; Jin et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect with decreased enzyme activity and reduced secretion of the protein (Chan et al., 2002); This variant is associated with the following publications: (PMID: 33303402, 32041611, 31980526, 24646025, 26079787, 17476032, 12204001, 27055971, 12905705, 27206937, 30420299)

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 98 of the LPL protein (p.Ala98Thr). This variant is present in population databases (rs145657341, gnomAD 0.2%). This missense change has been observed in individual(s) with chylomicronemia (PMID: 24646025, 38025240). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as A71T. ClinVar contains an entry for this variant (Variation ID: 1203042). 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 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: 12204001, 12905705). For these reasons, this variant has been classified as Pathogenic.

Variant summary: LPL c.292G>A (p.Ala98Thr) results in a non-conservative amino acid change located in the N-terminal lipase domain (IPR033906) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251470 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency (0.0034), allowing no conclusion about variant significance. c.292G>A (aka. Ala71Thr) has been reported in the literature in multiple heterozygous individuals affected with hypertriglyceridemia (e.g. Chan_2002, Yang_2003, Hu_2007, Chen_2014, Khovidhunkit_2015, Dron_2020), in addition, it was also found in compound heterozygous state (with another pathogenic variant in trans) in two individuals in a family, who manifested a more severe disease phenotype corresponding to recessive Familial Lipoprotein Lipase Deficiency (Chen_2014). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated a decreased specific activity, together with reduced secretion for the variant protein (Chan_2002, Yang_2003). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The LPL c.292G>A variant is predicted to result in the amino acid substitution p.Ala98Thr. This variant is also described using legacy nomenclature as p.Ala71Thr, has been reported in the heterozygous state in several individuals with hypertriglyceridemia with or without acute pancreatitis (Chan et al. 2002. PubMed ID: 12204001; Yang et al. 2003. PubMed ID: 12905705; Hu et al. 2007. PubMed ID: 17476032; Khovidhunkit et al. 2015. PubMed ID: 27206937). This variant has also been reported in the homozygous or compound heterozygous states in several individuals with hypertriglyceridemia with or without acute pancreatitis (Chen et al. 2014. PubMed ID: 24646025; Xie et al. 2015. PubMed ID: 26079787; Jin et al. 2018. PubMed ID: 30420299. Table S2; Ariza et al. 2019. PubMed ID: 31669931). Functional studies suggest that this variant results in reduced LPL protein activity, however LPL activity appeared normal in several individuals harboring this variant (Chan et al. 2002. PubMed ID: 12204001; Yang et al. 2003. PubMed ID: 12905705; Chen et al. 2014. PubMed ID: 24646025). This variant was reported as uncertain (Rodrigues et al. 2016. PubMed ID: 27055971; Jin et al. 2018. PubMed ID: 30420299. Table S2; Dron et al. 2020. PubMed ID: 32041611. Table S4). However, it was interpreted as likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1203042/). Taken together, this variant is interpreted as likely pathogenic.

PM2_Supporting+PP3+PM3_Strong

The p.A98T variant (also known as c.292G>A), located in coding exon 3 of the LPL gene, results from a G to A substitution at nucleotide position 292. The alanine at codon 98 is replaced by threonine, an amino acid with similar properties. This variant was found to be compound heterozygous with LPL p.L279V (c.835C>G) in a mother and daughter with severe hypertriglyceridemia, acute pancreatitis, and reduced plasma LPL activity (Chen TZ et al. Lipids Health Dis, 2014 Mar;13:52), and with LPL p.L279R (c.836T>G) in a different individual with severe hypertriglyceridemia (Jin JL et al. EBioMedicine, 2018 Dec;38:171-177). This variant was also detected in the homozygous state in an individual with severe hypertrigylceridemia (Ariza MJ et al. Clin Chim Acta, 2020 Jan;500:163-171). Additionally, this variant has been detected in several heterozygotes with hypertriglyceridemia with or without acute pancreatitis (Chan LY et al. Hum Mutat, 2002 Sep;20:232-3; Yang T et al. Hum Mutat, 2003 Apr;21:453; Hu Y et al. J Lipid Res, 2007 Aug;48:1681-8; Xie SL et al. PLoS One, 2015 Jun;10:e0129488; Khovidhunkit W et al. J Clin Lipidol Nov;10:505-511.e1). Functional studies indicate that this variant results in a significant reduction in LPL activity in vitro (Chan LY et al. Hum Mutat, 2002 Sep;20:232-3; Yang T et al. Hum Mutat, 2003 Apr;21:453). 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; however, it may represent a hypomorphic allele that results in later onset and a milder disease course.