ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1775G>A (p.Gly592Glu) (rs137929307)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000172964 SCV000212140 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844730 SCV000271385 pathogenic Familial hypercholesterolemia - homozygous 2015-11-17 criteria provided, single submitter clinical testing The p.Gly592Glu variant in LDLR has been reported in >200 Caucasian individuals with familial hypercholesterolemia (FH) and segregated with disease in >30 affec ted relatives from >3 families (Gorski 1998, Miltiadous 2001, Kuhrova 2002, Kubl aska 2008, Bourbon 2008, Chmara 2010, Diakou 2011, Tichy 2012, Bertolini 2013, D o 2015, Medeiros 2015, Jannes 2015, Braenne 2015). This variant has also been id entified in 15/126710 European chromosomes by the Genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org; dbSNP rs137929307). However, this frequ ency is low enough to be consistent with the frequency of FH in the general popu lation. Furthermore, in vitro functional studies provide some evidence that the p.Gly592Glu variant may impact protein function (Romano 2011). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholeste rolemia in an autosomal dominant manner based upon presence in multiple affected individuals and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong .
LDLR-LOVD, British Heart Foundation RCV000172964 SCV000295649 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000172964 SCV000322975 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/220 non-FH alleles; 0/77 healthy control individuals
Robarts Research Institute,Western University RCV000172964 SCV000484718 likely pathogenic Familial hypercholesterolemia 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 RCV000172964 SCV000503412 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 11 , family members = 3 with co-segregation / previously described in association with FH, 5 to 15% LDLR Activity/software prediction damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000172964 SCV000540837 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000587007 SCV000544669 pathogenic Familial hypercholesterolemias 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 592 of the LDLR protein (p.Gly592Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs137929307, ExAC 0.009%). This variant is clearly defined as a familial hypercholesterolemia causative allele (PMID: 15864114,20663204, 21310417), and is a common cause of familial hypercholesterolemia in individuals of European ancestry (PMID: 26238499, 23375686, 21925044), This variant is also known as p.Gly571Glu in the literature. ClinVar contains an entry for this variant (Variation ID: 161271). 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000162001 SCV000582282 pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing The G592E variant in the LDLR gene, previously reported as G571E due to alternate nomenclature, has been reported many times in association with heterozygous FH and homozygous FH (Hobbs et al., 1992; Chmara et al., 2010; Goldman et al., 2010; Bertolini et al., 2013; Mollaki et al., 2014; Braenne et al., 2016; Gabcova et al., 2017). The G592E variant is observed in 15/126,710 (0.01%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The G592E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies demonstrate that this variant would lead to deficient LDLR protein (Susan-Resiga et al., 2017).
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000172964 SCV000583883 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000172964 SCV000588605 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000172964 SCV000607638 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000587007 SCV000697209 pathogenic Familial hypercholesterolemias 2016-09-13 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1775G>A (p.Gly592Glu) variant involves the alteration of a conserved nucleotide. Gly592 is highly conserved across species, and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 6/121608 control chromosomes at a frequency of 0.0000493, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). This variant has been reported in many FH patients in both heterozygous, compound heterozygous, and homozygous states with evidence of co-segregation in some of the families. Functional studies indicate that the variant of interest has defective LDL receptor activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Iberoamerican FH Network RCV000172964 SCV000748115 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000172964 SCV000778604 pathogenic Familial hypercholesterolemia 2018-02-27 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000162001 SCV000888163 pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000172964 SCV000894177 pathogenic Familial hypercholesterolemia 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000587007 SCV000903573 pathogenic Familial hypercholesterolemias 2018-05-09 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as p.Gly571Glu in the mature protein and as FH-Sicily, FH Foggia-1, FH Naples) is a missense variant located in the fifth LDLR type B repeat of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental study has shown that this variant results in a partial loss of LDLR activity (PMID: 21865347). The variant has been identified in over 200 heterozygous and homozygous familial hypercholesterolemia patients from multiple European ethnicities (PMID: 1301956, 9654205, 11139254, 11139254, 11317361, 11641914, 11754108, 15199436, 15241806, 17765246, 18263977, 20145306, 20663204, 21310417, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417). Specially this variant is highly recurrent in Slovakia, Czech Republic, and Poland (PMID: 26238499). This variant has been identified in 16/277218 chromosomes (15/126710 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000172964 SCV000987017 pathogenic Familial hypercholesterolemia 2018-10-29 criteria provided, single submitter clinical testing This nucleotide substitution causes an exchange of the amino acid of glycine (Gly) to glutamic acid (Glu) p.Gly592Glu (legacy name: p.Gly571Glu). This change has already been described in the literature as FH Sicily, FH Foggia 1 and FH Naples 4 and has been found in patients with familial hypercholesterolemia and is associated with elevated cholesterol and LDL-C levels. It results in a reduced amount of biologically active LDL receptors on the cell surface. We observed this variant in a patient with TC up to 350 mg/dl and LDL-C approx 290 mg/dl at the age of 48 and in a patient with TC up to 300 mg/dl and LDL-C approx 250 mg/dl at the age of 5. PMID: 1301956, 27998977, 22390909, 26036859.
UCSF Pediatric Lipid Clinic, University of California, San Francisco RCV000172964 SCV000998546 pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing The p.G592E variant in LDLR segregates with elevated level of LDL-C in a family of over ten individuals. The allele frequency of this variant in the population is 0.00004 based on the GnomAD database.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162001 SCV000189576 not provided not provided no assertion provided in vitro
CSER_CC_NCGL; University of Washington Medical Center RCV000148576 SCV000190290 pathogenic Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000172964 SCV000268637 pathogenic Familial hypercholesterolemia 2010-09-07 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000172964 SCV000606511 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000172964 SCV000733827 likely pathogenic Familial hypercholesterolemia no assertion criteria provided clinical testing

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