ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1102T>C (p.Cys368Arg) (rs879254791)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Robarts Research Institute,Western University RCV000408876 SCV000484748 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000408876 SCV000583788 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV000408876 SCV000818723 pathogenic Familial hypercholesterolemia 1 2018-04-25 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 368 of the LDLR protein (p.Cys368Arg). 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 to segregate with familial hypercholesterolemia in a family and in an unrelated individual (PMID: 9452094, 27765764). This variant is also known as p.Cys347Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 369848). 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). 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. A different missense substitution at this codon (p.Cys368Tyr, also known as p.Cys347Tyr in the literature) has been determined to be pathogenic (PMID: 1301940, 25461735, 26081744). This suggests that the cysteine residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000408876 SCV000987459 pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000408876 SCV001432591 pathogenic Familial hypercholesterolemia 1 2019-05-10 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000408876 SCV000606327 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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