ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.427T>C (p.Cys143Arg) (rs875989901)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237201 SCV000294704 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237201 SCV000322898 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237201 SCV000540715 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys128 and Cys143.
Fulgent Genetics,Fulgent Genetics RCV000237201 SCV000894166 pathogenic Familial hypercholesterolemia 1 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000775039 SCV000909136 likely pathogenic Familial hypercholesterolemia 2019-03-12 criteria provided, single submitter clinical testing
Invitae RCV000775039 SCV001580452 pathogenic Familial hypercholesterolemia 2020-03-22 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 143 of the LDLR protein (p.Cys143Arg). 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 in individual(s) with familial hypercholesterolemia (PMID: 11462246, 22698793, 20828696, Invitae). This variant is also known as C122R in the literature. ClinVar contains an entry for this variant (Variation ID: 251219). 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). 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. For these reasons, this variant has been classified as Pathogenic.

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