ClinVar Genomic variation as it relates to human health

The LPL c.249+1G>A variant has been reported in multiple individuals with autosomal recessive lipoprotein lipase deficiency (PMID: 1752947, 24793350, 27055971). Unpublished data has demonstrated aberrant splicing resulting in decreased levels of LPL mRNA due to this variant (PMID: 1752947). In the heterozygous state, variants like this are associated with significantly elevated triglyceride levels and pancreatitis, especially with other comorbidities such as uncontrolled diabetes mellitus. This variant is not reported in the gnomAD population database . It was identified in an individual with a personal and family history of severe hypertriglyceridemia. Therefore, the LPL c.249+1G>A variant is classified as pathogenic.

The c.249+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the LPL gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. This variant has been detected in the homozygous state and in the compound heterozygous state with a second LPL variant in several unrelated individuals with features consistent with LPL deficiency and familial chylomicronemia syndrome (Gotoda T et al. J Clin Invest, 1991 12;88:1856-64; Chokshi N et al. J Clin Lipidol, 2014 Feb;8:287-95; Rodrigues R et al. J Clin Lipidol, 2016 Dec;10:394-409; Kuthiroly S et al. Indian J Pediatr, 2021 02;88:147-153). One study reportedly demonstrated that this variant resulted in aberrant splicing and decreased LPL mRNA in an affected patient; however, the results were unpublished (Gotoda T et al. J Clin Invest, 1991 12;88:1856-64). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LPL are known to be pathogenic (PMID: 11334614). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individuals affected with LPL-related conditions (PMID: 1752947, 24793350). ClinVar contains an entry for this variant (Variation ID: 1535). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 2 of the LPL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.