ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg)

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Total submissions: 16
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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 2020-01-07 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 observed in several individuals affected with familial hypercholesterolemia (PMID: 27206935, 17087781, 23064986, 21376320, 17765246, 17765246, 11810272, 17765246, 30592178). This variant is also known as p.Gly457Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 161277). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Gly478 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 27824480), which suggests that this may be a clinically significant amino acid residue. 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 Health, Inc RCV000775069 SCV000909170 likely pathogenic Familial hypercholesterolemia 2020-02-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826171 SCV000967710 likely pathogenic Homozygous familial hypercholesterolemia 2019-03-26 criteria provided, single submitter clinical testing The p.Gly478Arg (also called p.Gly457Arg) variant in LDLR has been reported in the heterozygous state in >15 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, ClinVar: Variation ID 161277). The variant has also been reported in two individuals who were compound heterozygous for this variant and a second variant in LDLR (Mak 1998, Chiou 2010). Additionally, another nucleotide change (c.1432G>C) leading to the same amino acid 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 provide some evidence that the p.Gly478Arg variant may impact protein function (Hobbs 1992). This variant has been also been identified in 2/17246 East Asian chromosomes and 2/16208 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Gly478Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly478Arg variant is likely pathogenic. The ACMG/AMP criteria applied: PS4, PP1, PP3, PS3_Supporting.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256967 SCV001433509 likely pathogenic not provided 2019-09-24 criteria provided, single submitter clinical testing
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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