ClinVar

Description

This variant is an in-frame deletion of the genomic region encompassing exons 3-6 of the LDLR gene. It preserves the integrity of the reading frame. Similar deletions of exons 3-6 have been reported to segregate with familial hypercholesterolemia in a family and have been reported in unrelated individuals affected with this condition (PMID: 1863993, 23375686, 17399720, 16250003, 19538517). This variant affects an LDLRA domain of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). While functional studies have not been performed to directly test the effect of this variant on LDLR protein function, this suggests that disruption of this region of the protein is causative of disease. Several different missense substitutions (p.Cys116Arg, p.Asp266Glu, p.Cys313Tyr) have been determined to be pathogenic (PMID: 11668640, 10634824, 25545329, 1301956, 20663204, 22698793, 9259195, 9698020, 11810272) in this deleted region. This suggests that exons 3-6 are critical for LDLR protein function and that this deletion may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.