Submissions for variant NM_000527.5(LDLR):c.805_813del (p.Gly269_Val271del)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581547	SCV004369617	pathogenic	Familial hypercholesterolemia	2023-07-10	criteria provided, single submitter	clinical testing	This variant, c.805_813del, results in the deletion of 3 amino acid(s) of the LDLR protein (p.Gly269_Val271del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains 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 and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts a region of the LDLR protein in which other variant(s) (p.Cys270Tyr) have been determined to be pathogenic (PMID: 1301956, 7903864, 15637307, 23375686, 29233637, 30270083). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.