Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000238269 | SCV000295809 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
RCV000238269 | SCV000322995 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | 0/200 non-FH alleles |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000238269 | SCV000503449 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1/software prediction damaging |
Molecular Genetics Laboratory, |
RCV000238269 | SCV000540851 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | Disrupt disulfide bridge between Cys667 and Cys681. |
Laboratory of Genetics and Molecular Cardiology, |
RCV000238269 | SCV000588626 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Iberoamerican FH Network | RCV000238269 | SCV000748170 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Invitae | RCV000821494 | SCV000962252 | pathogenic | Familial hypercholesterolemia | 2019-12-20 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine with arginine at codon 667 of the LDLR protein (p.Cys667Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 9412789) and has been observed in individuals affected with familial hypercholesterolemia (PMID: 9412789, 23064986, 27824480, 21310417, 17765246). This variant is also known as p.Cys646Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 252163). This variant disrupts the p.Cys667 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15701167, 18263977, 23375686, 11313767, 9727746), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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). For these reasons, this variant has been classified as Pathogenic. |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238269 | SCV000606573 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research |