ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1048C>T (p.Arg350Ter) (rs769737896)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211692 SCV000295161 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211692 SCV000322924 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/100 healthy control individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211692 SCV000503287 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 4 , family member = 3 with co-segregation / FH-Fossum
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211692 SCV000540784 pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000211692 SCV000544687 pathogenic Familial hypercholesterolemia 1 2018-05-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 350 (p.Arg350*) 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 (PMID: 20809525). This particular variant has been reported in numerous individuals and families affected with familial  hypercholesterolemia (PMID: 7709162, 9039985, 22390909, 21382890, 21310417), and has been reported in an individual affected with myocardial infarction (PMID: 25487149). This variant is also known as Arg329* in the literature. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000211692 SCV000588544 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000211692 SCV000607550 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
GeneDx RCV000520229 SCV000617506 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing The R350X variant in the LDLR gene (also reported as FH Fossum and R329X due to the use of alternate nomenclature) has been identified in many individuals with FH from various ethnic backgrounds, and has been shown to segregate with FH in affected family members (Solberg et al., 1994; Lombardi et al., 1995; Day et al., 1997; Gorski et al., 1998; Gaudet et al., 1999; Maruyama et al., 2004; Bourbon et al., 2008; Kubalska et al., 2008; Alonso et al., 2009; Chmara et al., 2010; van der Graaf et al., 2011; Futema et al., 2012; Bertolini et al., 2013; Jannes et al., 2015; Fan et al., 2015; Hu et al., 2016). R350X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014). Furthermore, the R350X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Color RCV000771543 SCV000904104 pathogenic Familial hypercholesterolemia 2017-07-24 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as p.Arg329X and FH-Fossum) changes one nucleotide in exon 7 of the LDLR mRNA. This creates a premature translational stop signal and is expected to result in an absent or non-functional protein product. Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). While this variant is rare in the general population (0/277264 chromosomes by the Genome Aggregation Database (gnomAD)), it has been identified in numerous individuals affected with familial hypercholesterolemia (PMID: 7709162, 9039985, 21382890, 21310417, 22390909, 27680772, 28235710). It has also been reported in an individual affected with myocardial infarction (PMID: 25487149). Based on available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000520229 SCV001134245 pathogenic not provided 2019-02-05 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211692 SCV000268595 pathogenic Familial hypercholesterolemia 1 2008-06-05 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211692 SCV000606298 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000211692 SCV000733817 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided clinical testing

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