ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.283T>G (p.Cys95Gly) (rs879254456)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238124 SCV000294577 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000238124 SCV000607439 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000238124 SCV000627035 pathogenic Familial hypercholesterolemia 2017-08-04 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 95 of the LDLR protein (p.Cys95Gly). 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 reported in multiple unrelated individuals affected with familial hypercholesterolemia (PMID: 15241806, 18718593, 19007590, 21955034). This variant is also known as p.Cys74Gly in the literature. ClinVar contains an entry for this variant (Variation ID: 251112). Algorithms developed to predict the effect of missense changes on protein structure and function 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 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: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238124 SCV000606062 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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