ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2029T>C (p.Cys677Arg) (rs775092314)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211671 SCV000295824 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211671 SCV000484752 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Invitae RCV000791370 SCV000830362 pathogenic Familial hypercholesterolemia 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 677 of the LDLR protein (p.Cys677Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs775092314, ExAC 0.002%). This variant has been observed to segregate with hypercholesterolemia in a family (PMID: 19487412). It has also been reported in several unrelated individuals with hypercholesterolemia (PMID: 1301956, 22883975, 17142622, 27680772, 27765764, 10208479). This variant is also known as p.Cys656Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 226384). 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. The p.Cys677 amino acid residue in LDLR has been determined to be clinically significant (PMID: 16389549, 9763532, 28235710). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000211671 SCV000839986 likely pathogenic Familial hypercholesterolemia 1 2018-04-13 criteria provided, single submitter clinical testing This c.2029T>C (p.Cys677Arg) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 10208479, 10559517) or myocardial infarction (PMID 25487149). Functional studies have indicated that the p.Cys677Arg variant in the LDLR protein has 5-15% receptor activity compared to wild-type LDLR protein (PMID: 1301956). The c.2029T>C variant is rare in the general population and cysteine at position 677 of the LDLR protein is highly evolutionarily conserved. The c.2029T>C (p.Cys677Arg) variant in the LDLR gene is classified as likely pathogenic.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211671 SCV000268653 pathogenic Familial hypercholesterolemia 1 2008-06-05 no assertion criteria provided clinical testing

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