ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.244T>G (p.Cys82Gly)

dbSNP: rs879254447
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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 RCV000237614 SCV000294550 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237614 SCV000503117 likely pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2/previously described in association with FH / Software predictions: Damaging
Labcorp Genetics (formerly Invitae), Labcorp RCV001857820 SCV002174214 pathogenic Familial hypercholesterolemia 2021-12-04 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 28964736). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 82 of the LDLR protein (p.Cys82Gly). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 251091). 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). This variant disrupts the p.Cys82 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

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