ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1646G>A (p.Gly549Asp)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003886 SCV000295560 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000003886 SCV000484682 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 RCV000003886 SCV000503381 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 4 , family member = 1 with co-segregation / FH-Palermo, 2% LDLR activity / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003886 SCV000540828 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000587938 SCV000544685 pathogenic Familial hypercholesterolemia 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 549 of the LDLR protein (p.Gly549Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs28941776, ExAC 0.009%). This variant is clearly defined as a familial hypercholesterolemia causative allele (PMID: 23375686, 25487149). It is a common cause of familial hypercholesterolemia in individuals of Italian ancestry. This variant is also known as p.Glu528Asp in the literature. ClinVar contains an entry for this variant (Variation ID: 3698). Experimental studies have shown that this missense change inhibits the transport of the LDLR protein to the cellular surface (PMID: 25647241). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003886 SCV000583858 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000003886 SCV000588600 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000003886 SCV000607619 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587938 SCV000697207 pathogenic Familial hypercholesterolemia 2017-03-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000003886 SCV000894176 pathogenic Familial hypercholesterolemia 1 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000587938 SCV001346737 pathogenic Familial hypercholesterolemia 2021-02-18 criteria provided, single submitter clinical testing This missense variant (also known as p.Gly528Asp in the mature protein and as FH Genoa, FH Palermo-1) is located in the fourth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). Experimental functional studies have shown that this variant causes defective LDLR protein transport (PMID: 2088165) and results in <2-5% LDLR activity (PMID: 1301956, 25647241). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 8683740, 9259195, 9544850, 11810272, 15241806, 23375686) and particularly common in Greek (PMID: 8683740) and Italian populations (PMID: 23375686). This variant has been identified in 6/246260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000003886 SCV001433282 pathogenic Familial hypercholesterolemia 1 2020-02-11 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000587938 SCV001435010 pathogenic Familial hypercholesterolemia 2018-08-06 criteria provided, single submitter clinical testing The c.1646G>A (p.Gly549Asp) variant has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID 1301956,9259195, 9544850, 11810272, 15199436, 15241806, 19837725, 21865347, 23375686) or myocardial infarction (PMID 25487149). A functional study reported the mutant LDLR protein retains less than 2 percent receptor activity compared to wild type LDLR protein (PMID 1301956) and the variant is classified as 'disruptive' through systematic cell-based phenotyping (PMID 25647241). Therefore, this c.1646G>A (p.Gly549Asp) variant is classified as pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II RCV000003886 SCV001653643 pathogenic Familial hypercholesterolemia 1 2021-05-24 criteria provided, single submitter clinical testing Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.
Mayo Clinic Laboratories, Mayo Clinic RCV000161997 SCV001715493 pathogenic not provided 2020-07-02 criteria provided, single submitter clinical testing
GeneDx RCV000161997 SCV001782225 pathogenic not provided 2020-12-18 criteria provided, single submitter clinical testing Also reported as FH Genoa, FH Palermo-1, and G528D due to alternate nomenclature; Published functional studies demonstrate a damaging effect with abnormal LDL transport/uptake and significantly reduced receptor activity (Hobbs et al., 1990; Romano et al., 2011; Thormaehlen et al., 2015; Rodriguez-Jimenez et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#3698; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32770674, 32041611, 32977124, 31106925, 31447099, 29874871, 27578104, 25463123, 21310417, 21925044, 22371747, 19837725, 19717150, 19446849, 15241806, 15199436, 11317361, 9544850, 9259195, 2088165, 20045108, 28391899, 21865347, 25525159, 25647241, 25487149, 23375686, 28965616, 33093846)
OMIM RCV000003886 SCV000024051 pathogenic Familial hypercholesterolemia 1 1988-11-01 no assertion criteria provided literature only
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161997 SCV000189572 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003886 SCV000606474 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000003886 SCV000733824 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided clinical testing
Iberoamerican FH Network RCV000003886 SCV000748175 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 no assertion criteria provided research
Clinical Genetics,Academic Medical Center RCV000161997 SCV001925125 pathogenic not provided no assertion criteria provided clinical testing

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