Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000238515 | SCV000294552 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Invitae | RCV002229813 | SCV000825602 | pathogenic | Familial hypercholesterolemia | 2018-05-03 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine with phenylalanine at codon 82 of the LDLR protein (p.Cys82Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypercholesterolemia (PMID: 12417285). This variant is also known in the literature as p.Cys61Phe. ClinVar contains an entry for this variant (Variation ID: 251093). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The observation of one or more missense substitutions at this codon (p.Cys82Gly, p.Cys82Tyr, p.Cys82Ser) in affected individuals suggests that this may be a clinically significant residue (PMID: 20809525, 11196104, 25461735). For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within 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). |