ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2043C>A (p.Cys681Ter)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000003887 SCV000264002 pathogenic Familial hypercholesterolemia 1 2015-11-02 criteria provided, single submitter clinical testing
Invitae RCV000590806 SCV000285024 pathogenic Familial hypercholesterolemia 2019-10-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys681*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121908031, ExAC 0.002%). This variant has been observed to segregate with familial hypercholesterolemia in several families and has been reported in multiple unrelated individuals with this disease (PMID: 22487947, 1959928, 19319977, 21145767, 11668627, 25461735). This variant is also known as p.Cys660* in the literature. ClinVar contains an entry for this variant (Variation ID: 3699). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000003887 SCV000295837 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000003887 SCV000484730 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 RCV000003887 SCV000503452 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 31 (1 homozygote) , family members = 17 with co-segregation / FH-Libanon, < 2% LDLR Activity
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003887 SCV000540853 pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
GeneDx RCV000481771 SCV000568525 pathogenic not provided 2018-09-10 criteria provided, single submitter clinical testing The C681X pathogenic variant in the LDLR gene (also reported as C660X due to alternate nomenclature) has been reported many times in both the heterozygous and homozygous states in individuals with FH (Lehrman et al., 1987; Day et al., 1997; Callis et al., 1998; Xenophontos et al., 2000; Wang et al., 2001; Bodamer et al., 2002; Dedoussis et al., 2004). The C681X variant is considered a Lebanese founder mutation and may account for greater than 80% of FH cases in this population (Abifadel et al., 2009). Furthermore, the C681X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Located in the middle of a cysteine-rich sequence that is part of the epidermal growth factor precursor homology domain, C681X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay (Lehrman et al., 1987). In addition, other nonsense variants in the LDLR gene have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014).
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003887 SCV000583922 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000003887 SCV000588629 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000003887 SCV000607668 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000590806 SCV000697220 pathogenic Familial hypercholesterolemia 2016-10-26 criteria provided, single submitter clinical testing Variant summary: The LDLR c.2043C>A (p.Cys681X) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified in the pathogenic spectrum by our laboratory (e.g. p.Trp813X, p.Ser710fsX2 ). Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121136 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). It was observed in several FH families and showed co-segregation with the disease indicating causality. Moreover, the variant was shown to result in lack of detectable high affinity binding and uptake of LDL, further supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844750 SCV000731826 pathogenic Homozygous familial hypercholesterolemia 2017-08-11 criteria provided, single submitter clinical testing The p.Cys681X variant in LDLR has been reported in >80 individuals with hypercho lestrolemia across several studies and segregated with disease in >10 affected r elatives (Abifadel 2009, Banares 2017, Fahed 2011, Jannes 2015, Lehrman 1987, Ti chy 2012, Vandrovcova 2013). This variant is considered to be a founder variant in the Lebanese population (Fahed 2016). This variant has also been reported i n Clinvar (Variation ID 3699) and identified in 1/33580 Latino and 1/111664 Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs121908031). This nonsense variant leads to a premature te rmination codon at position 681, which is predicted to lead to a truncated or ab sent protein. Heterozygous loss of function of the LDLR gene is an established d isease mechanism in familial hypercholestrolemia. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholestrolemia in an autosomal dominant manner based upon frequency in affected individuals and segre gation studies.
Iberoamerican FH Network RCV000003887 SCV000748104 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Gharavi Laboratory,Columbia University RCV000481771 SCV000809473 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Fulgent Genetics,Fulgent Genetics RCV000003887 SCV000894178 pathogenic Familial hypercholesterolemia 1 2018-10-31 criteria provided, single submitter clinical testing
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000003887 SCV000987033 pathogenic Familial hypercholesterolemia 1 2018-08-09 criteria provided, single submitter clinical testing The nucleotide substitution c.2043C> A leads to a premature termination of protein synthesis at position 681 and is described as "FH Lebanese allele" in the literature. The mutation leads to intracellular degradation of the LDL receptor and loss of function. The mutation described here has also been described in patients with hypercholesterolemia and is therefore classified as pathogenic. PMID: 1453433, 3025214
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000003887 SCV000987528 pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481771 SCV001134256 pathogenic not provided 2018-10-19 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Color RCV000590806 SCV001352605 pathogenic Familial hypercholesterolemia 2018-12-31 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000003887 SCV001432604 pathogenic Familial hypercholesterolemia 1 2019-05-11 criteria provided, single submitter research
OMIM RCV000003887 SCV000024052 pathogenic Familial hypercholesterolemia 1 1991-11-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003887 SCV000268655 pathogenic Familial hypercholesterolemia 1 2012-05-04 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003887 SCV000606582 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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