ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1432G>A (p.Gly478Arg) (rs144614838)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomarker Research Laboratory,Mayo Clinic RCV000211688 SCV000266307 likely pathogenic Familial hypercholesterolemia 1 2015-08-31 criteria provided, single submitter research MAF =<0.3%, likely pathogenic based on the integrative in-silico score, DLCN criteria >=3; LDL-C >=160 mg/dL, previously reported as P/LP in the literature
LDLR-LOVD, British Heart Foundation RCV000211688 SCV000295428 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211688 SCV000322952 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/208 non-FH alleles; 0/50 normolipidemic individuals; 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 RCV000211688 SCV000503348 uncertain significance Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / FH-New-York-2, 5 to 15% LDLR activity/Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211688 SCV000540818 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211688 SCV000583830 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000211688 SCV000588579 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000211688 SCV000607597 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000775069 SCV000832839 likely pathogenic Familial hypercholesterolemia 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 478 of the LDLR protein (p.Gly478Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs144614838, ExAC 0.01%). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 27206935, 17087781, 23064986, 21376320, 17765246, 17765246,  11810272, 17765246). This variant is also known as p.Gly457Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 161277). Different missense substitutions at this codon (p.Gly478Glu and p.Gly478Arg) have been reported in an individuals affected with familial hypercholesterolemia (PMID: 27824480, 28126585). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000211688 SCV000839985 likely pathogenic Familial hypercholesterolemia 1 2017-09-19 criteria provided, single submitter clinical testing This c.1432G>A (p.Gly478Arg) variant in the LDLR gene has been reported in multiple patients with familial hypercholesterolemia (PMID: 1301956, 7573037, 9763532, 11810272). Functional studies have indicated that the p.Gly478Arg variant LDLR protein has 2-5% receptor activity compared to wild-type LDLR protein (PMID: 1301956). The c.1432G>A variant is extremely rare in the general population and glycine at position 478 of the LDLR protein is highly evolutionarily conserved. The c.1432G>A (p.Gly478Arg) variant in the LDLR gene is classified as likely pathogenic.
Color RCV000775069 SCV000909170 likely pathogenic Familial hypercholesterolemia 2018-08-18 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as p.Gly457Arg in the mature protein and as FH New York-2, FH Fin-9) is located in the second LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional study has suggested that this variant may cause significant defect in protein transport or recycling (PMID: 1301956). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 1301956, 7573037, 9763532, 11810272, 22883975, 25618577). This variant has also been shown to segregate with disease in 6 affected individuals from two families (4 unaffected non-carriers) (PMID: 24627126). This variant has been identified in 5/246070 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826171 SCV000967710 likely pathogenic Familial hypercholesterolemia - homozygous 2018-07-20 criteria provided, single submitter clinical testing The p.Gly478Arg (also called p.Gly457Arg) variant in LDLR has been reported in t he heterozygous state in at least 11 individuals with hypercholesterolemia, and segregated with disease in at least 4 relatives from these families (Hobbs 1992, Koivisto 1995, Bourbon 2008, Alonso 2009, Ahmad 2012, Hooper 2012, Lange 2014, Safaro 2017). The variant has also been reported in two individuals who were com pound heterozygous for this variant and a second variant in LDLR (Mak 1998, Chio u 2010). This variant has also been reported in ClinVar (Variation ID# 161277). Additionally, another nucleotide change (c.1432G>C) leading to the same amino ac id change has been reported in 2 individuals with FH, one of whom was homozygous for the variant (Fouchier 2005, Widhalm 2017). In vitro functional studies prov ide some evidence that the p.Gly478Arg variant may impact protein function (Hobb s 1992). However, these types of assays may not accurately represent biological function. This variant has been identified in 2/17246 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Comp utational prediction tools and conservation analysis suggest that the p.Gly478Ar g variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, although additional studies are requi red to fully establish its clinical significance, the p.Gly478Arg variant is lik ely pathogenic. ACMG/AMP criteria applied: PM2, PS4_Moderate, PP1, PP3, PS3_Supp orting.
CSER _CC_NCGL, University of Washington RCV000148583 SCV000190297 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211688 SCV000268615 pathogenic Familial hypercholesterolemia 1 2008-06-27 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211688 SCV000606423 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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