ClinVar

Description

Variant summary: ABCA1 c.254C>T (p.Pro85Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 258052 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 112.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA1 causing Early Onset Coronary Artery Disease phenotype (1.3e-05), strongly suggesting that the variant is benign. The variant has been reported in the literature in the heterozygous state only (or unstated), in individuals with low HDL-C, FH, MI and hypoalphalipoproteinemia (Colin_2014, Beaudoin_2012, Luirink_2019, Geller_2018, Dong_2022), and in some tested individuals was associated with lower HDL-C levels (Cohen_2004), without strong evidence for causality. The variant was found in at least 1 pt with critically low HDL and personal history of CAD, however 4 additional family members who carried this variant heterozygously presented only with hypoalphalipoproteinemia but were cardiologically normal (Hong et al.,2002). In at least 1 large scale genome sequencing project, the variant was not associated with HDL-C levels (Morrison_2013) and was reported as 'polymorphism' by Kiss et. al, 2007. These reports do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. In addition, cholesterol efflux was found to be higher in cells from an individual with the variant compared to normal controls, while other variants associated with lower HDL-C levels had cholesterol efflux levels less than two standard deviations below the mean in subjects with normal HDL-C (Cohen_2004). 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. Two submitters have classified the variant as likely benign, while two classified as VUS and one classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign.