ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2215C>T (p.Gln739Ter) (rs370018159)

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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 RCV000237494 SCV000295919 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237494 SCV000484732 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237494 SCV000503474 uncertain significance Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1/FH-Japan
Invitae RCV000791393 SCV000544653 pathogenic Familial hypercholesterolemia 2018-11-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 739 (p.Gln739*) of the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic. This particular variant has been reported in the literature in individuals with familial hypercholesterolemia (PMID: 12417285, 20045108, 20538126, 21376320, 23375686). This variant is also known as p.Gln718X in the literature. For these reasons, this variant has been classified as Pathogenic.
Color RCV000791393 SCV001356940 pathogenic Familial hypercholesterolemia 2018-12-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000791393 SCV001361871 pathogenic Familial hypercholesterolemia 2019-10-29 criteria provided, single submitter clinical testing Variant summary: LDLR c.2215C>T (p.Gln739X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251316 control chromosomes (gnomAD). c.2215C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Yu_2002, Robles-Osorio_2006, Romano_2010, Chiou_2010, Pirillo_2017, Kolansky_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reported that the variant resulted in less than 2% of normal LDLR activity in patient derived skin fibroblasts (Kolansky_2008). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and as VUS (1x). Based on the evidence outlined above, the variant was classified as pathogenic.

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