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

Total submissions: 17

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	2020-08-14	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 C1). 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	2020-09-09	criteria provided, single submitter	clinical testing	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 suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a defect in protein transport and recycling, and a decreased LDLR activity (PMID: 1301956, 32695144). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 7573037, 9763532, 11810272, 22883975, 25618577, 32143996, 32220565, 32331935; Color internal data). In addition, this variant has been shown to segregate with disease in six affected individuals from two families and was absent in four unaffected family members (PMID: 24627126). This variant has been identified in 7/251112 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
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
GeneDx	RCV001256967	SCV001759852	likely pathogenic	not provided	2019-10-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar (ClinVar Variant ID#161277; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; A missense variant in the same residue (G478E), has been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014); however, the pathogenicty of this variant has not been definitively determined; This variant is associated with the following publications: (PMID: 31447099, 7573037, 17087781, 30526649, 19318025, 21376320, 27206935, 24507775, 1301956, 29245966, 29292049, 29874871, 29261184, 25637381, 24055113, 22883975, 20538126, 28126585, 9763532, 19118540, 28145427, 15556092, 17765246, 23064986, 27680772, 18325082, 30592178, 15199436, 11810272)
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