ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.939C>G (p.Cys313Trp) (rs13306512)

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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 RCV000237523 SCV000295074 likely pathogenic Familial hypercholesterolemia 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 RCV000237523 SCV000503258 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 3 , family members = 2 with co-segregation c.932A>G, c.939C>G / p.Lys311Arg, p.Cys313Trp systematicaly associated (Van Leuven et al. Atherosclerosis 2001) / Software predictions: Damaging
Invitae RCV000791350 SCV000830606 uncertain significance Familial hypercholesterolemia 2018-08-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 313 of the LDLR protein (p.Cys313Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is present in population databases (rs13306512, ExAC 0.01%). This variant has been reported in several individuals affected with hypercholesterolemia. This variant has been found in combination with p.Lys311Arg in some of these individuals (PMID: 11257257, 12436241, 20506408). This variant is also known as C292W in the literature. ClinVar contains entries for this variant (Variation ID: 251540, 430769). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237523 SCV000606276 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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