ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.664T>C (p.Cys222Arg) (rs577934998)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211577 SCV000294868 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211577 SCV000484706 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211577 SCV000503200 uncertain significance Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family member = 1 /FH-France / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211577 SCV000583716 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV000799446 SCV000939108 pathogenic Familial hypercholesterolemias 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 222 of the LDLR protein (p.Cys222Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs577934998, ExAC 0.01%). This variant has been observed in several individuals affected with hypercholesterolemia (PMID: 25043216, 22883975, 10532689, 15823276). This variant is also known in the literature as C201R and c.541T>C. ClinVar contains an entry for this variant (Variation ID: 226332). 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). This variant disrupts the p.Cys222 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 7573037, 24671153), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211577 SCV000268578 pathogenic Familial hypercholesterolemia 2008-06-05 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211577 SCV000606188 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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