Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000238124 | SCV000294577 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Fundacion Hipercolesterolemia Familiar | RCV000238124 | SCV000607439 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Invitae | RCV002229686 | SCV000627035 | pathogenic | Familial hypercholesterolemia | 2017-07-19 | criteria provided, single submitter | clinical testing | 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). For these reasons, this variant has been classified as Pathogenic. 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"). This variant has been reported in multiple unrelated individuals affected with familial hypercholesterolemia (PMID: 15241806, 18718593, 19007590, 21955034). This variant is also known as p.Cys74Gly in the literature. ClinVar contains an entry for this variant (Variation ID: 251112). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with glycine at codon 95 of the LDLR protein (p.Cys95Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238124 | SCV000606062 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |