ClinVar

Description

Variant summary: PLA2G7 c.663+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00096 in 251324 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency does not allow conclusions about variant significance. c.663+1G>A has been reported in the literature in individuals affected with Lipoprotein-associated phospholipase A2 (Lp-PLA2) Deficiency, an enzyme that hydrolyzes phospholipids to generate lysophosphatidylcholine and oxidized nonesterified fatty acids (example, Salaheen_2017). In observational epidemiologic studies, higher soluble Lp-PLA2 enzymatic activity has been correlated with increased risk for coronary heart disease; small molecule inhibitors of Lp-PLA2 have been developed for the treatment of coronary heart disease (Salaheen_2017 citing Di Angelantonio_2012). This study identified participants who are naturally deficient in the Lp-PLA2 enzyme including two homozygotes and 106 heterozygotes. A dose-dependent response relationship between genotype and enzymatic activity was observed, however, carriers of c.663+1G>A did not have a reduced risk of myocardial infarction (Salaheen_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Platelet-Activating Factor Acetylhydrolase Deficiency and an associated risk for myocardial infarction and/or stroke. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014. The clinical diagnostic laboratory classified the variant as a risk factor for coronary heart disease citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.