Submissions for variant NM_000237.3(LPL):c.292G>A (p.Ala98Thr)

gnomAD frequency: 0.00006  dbSNP: rs145657341

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001568938	SCV001792898	likely pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001568938	SCV002284257	likely pathogenic	not provided	2024-01-27	criteria provided, single submitter	clinical testing	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). 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). 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: 12204001, 12905705). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001827495	SCV002511433	likely pathogenic	Hyperlipoproteinemia, type I	2022-04-20	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002440807	SCV002748562	likely pathogenic	Cardiovascular phenotype	2024-02-20	criteria provided, single submitter	clinical testing	The c.292G>A (p.A98T) alteration is located in exon 3 (coding exon 3) of the LPL gene. This alteration results from a G to A substitution at nucleotide position 292, causing the alanine (A) at amino acid position 98 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.017% (48/282866) total alleles studied. The highest observed frequency was 0.165% (33/19950) of East Asian alleles. This variant has been identified in the homozygous state and in conjunction with another LPL variant in individuals with features consistent with chylomicronemia syndrome (Wu, 2023; Tong, 2022; Ariza, 2020; Jin, 2018; Chen, 2014). Additionally, this variant has been detected in several heterozygotes with hypertriglyceridemia with or without acute pancreatitis (Chan, 2002; Yang, 2003; Hu, 2007; Xie, 2015; Khovidhunkit, 2016). This amino acid position is highly conserved in available vertebrate species. Functional studies indicate that this variant results in a significant reduction in LPL activity in vitro (Chan, 2002; Yang, 2003). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002501917	SCV002813925	likely pathogenic	Hyperlipidemia, familial combined, LPL related; Hyperlipoproteinemia, type I	2022-02-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001568938	SCV003833473	likely pathogenic	not provided	2022-11-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003405720	SCV004113414	likely pathogenic	LPL-related disorder	2023-04-25	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001827495	SCV004805691	likely pathogenic	Hyperlipoproteinemia, type I	2024-09-02	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001827495	SCV002083203	likely pathogenic	Hyperlipoproteinemia, type I	2020-09-10	no assertion criteria provided	clinical testing