Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237110 | SCV000294742 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Invitae | RCV001236838 | SCV001409576 | pathogenic | Familial hypercholesterolemia | 2019-10-17 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys167 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11196104, 20809525), which suggests that this may be a clinically significant amino acid residue. 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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to segregate with familial hypercholesterolemia in a family (PMID: 11642133), and has been observed in an individual with clinical features of this condition (Invitae). This variant is also known as C146R in the literature. ClinVar contains an entry for this variant (Variation ID: 251255). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 167 of the LDLR protein (p.Cys167Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237110 | SCV000606135 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |