ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.346T>C (p.Cys116Arg) (rs879254482)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237774 SCV000294642 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000237774 SCV000607450 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000237774 SCV000816330 pathogenic Familial hypercholesterolemia 1 2018-03-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 116 of the LDLR protein (p.Cys116Arg). 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 reported in an individuals affected with Familial Hypercholesterolemia (FH) (PMID: 11668640, 10634824), and in several other individuals collected as part of FH cohorts. However, it was unclear if the phenotype of these individuals met FH diagnostic thresholds (PMID: 10206683, 23375686, 15241806).  This variant is also known as C95R in the literature. ClinVar contains an entry for this variant (Variation ID: 251163). This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain 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: 3495735, 4750422). In addition, missense substitutions within the LDLR EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Experimental studies have shown that this missense change affects the binding ability of the LDLR protein (PMID:  25545329). For these reasons, this variant has been classified as Pathogenic.

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