ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1999T>C (p.Cys667Arg) (rs150021927)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238269 SCV000322995 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/200 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238269 SCV000503449 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1/software prediction damaging
Iberoamerican FH Network RCV000238269 SCV000748170 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000821494 SCV000962252 pathogenic Familial hypercholesterolemias 2018-11-10 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.
LDLR-LOVD, British Heart Foundation RCV000238269 SCV000295809 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238269 SCV000606573 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000238269 SCV000588626 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000238269 SCV000540851 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys667 and Cys681.

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