ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.100T>G (p.Cys34Gly) (rs879254405)

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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 RCV000237876 SCV000294465 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237876 SCV000540717 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys34 and Cys52.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237876 SCV000583631 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing ACMG Guidelines: Pathogenic (ii)
Robarts Research Institute,Western University RCV000237876 SCV000782904 likely pathogenic Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Invitae RCV001230907 SCV001403407 pathogenic Familial hypercholesterolemia 2019-09-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 34 of the LDLR protein (p.Cys34Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families affected with familial hypercholesterolemia (PMID: 20809525, 26892515, 30592719, 27824480, 22698793). ClinVar contains an entry for this variant (Variation ID: 251018). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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