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

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211688	SCV002506334	pathogenic	Hypercholesterolemia, familial, 1	2021-12-14	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS4, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PP1_strong - variant segregates with FH phenotype in 10 informative meiosis from 4 families from 2 labs: - Laboratory of Genetics and Molecular Cardiology - Data from 1 family: 2 relatives positive for variant with LDL-C >75th percentile, 1 relative negative for variant with LDL-C <50th percentile; - Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - Data from 3 families. F1: 3 relatives with the phenotype are positive for the variant plus 1 relative without the phenotype is negative for the variant. F2: 1 relative with the phenotype and positive for the variant plus 1 relative without the phenotype is negative for the variant. F3: 1 relative with the phenotype is positive for the variant. so PP1_Strong is met PS4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs: - 1 case with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - 1 case with DLCN score >= 6 from Color Health, Inc; - 4 unrelated cases with DLCN score >= 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 4 unrelated cases with Simon-Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; - 1 case with DLCN score >= 6 from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), so PS4 is met PM2 - PopMax MAF = 0.0001234 (0.01234%) in African/African-American exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs (see details in PS4), so PP4 is met.
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000211688	SCV000266307	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211688	SCV000322952	uncertain significance	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211688	SCV000583830	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211688	SCV000588579	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211688	SCV000607597	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775069	SCV000832839	pathogenic	Familial hypercholesterolemia	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the LDLR protein (p.Gly478Arg). This variant is present in population databases (rs144614838, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17087781, 17765246, 21376320, 22353362, 23064986, 27206935, 30592178; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly457Arg. ClinVar contains an entry for this variant (Variation ID: 161277). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. 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. For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000211688	SCV000839985	likely pathogenic	Hypercholesterolemia, familial, 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 Diagnostics, LLC DBA Color Health	RCV000775069	SCV000909170	pathogenic	Familial hypercholesterolemia	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 478 and alters a conserved glycine residue in the second LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 439-485) where pathogenic missense variants are found enriched (ClinVar-LDLR). This variant is also known as p.Gly457Arg in the mature protein sequence and as FH New York-2 and FH Fin-9 in the literature. Computational prediction suggests that this variant may have a 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), as well as in 10 informative meiosis from 4 unpublished families (ClinVar variation ID: 161277; accession ID: SCV002506334.1). 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 Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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	pathogenic	not provided	2024-10-04	criteria provided, single submitter	clinical testing	Published functional studies suggest impaired LDLR localization and LDL uptake (PMID: 32695144); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as FH New York-2, FH Finn-9, and G457R; This variant is associated with the following publications: (PMID: 23064986, 24055113, 25637381, 30592178, 15199436, 11810272, 18325082, 27680772, 17765246, 15556092, 28145427, 19118540, 9763532, 20538126, 29245966, 22883975, 29261184, 29874871, 1301956, 24507775, 27206935, 21376320, 19318025, 30526649, 17087781, 7573037, 37409534, 36226792, 35130036, 35913489, 35480308, 33955087, 32220565, 8535447, 29292049, 31447099, 32331935, 33994402, 32143996, LinJL2022, 33740630, 34037665, 28126585, 32695144)
Revvity Omics, Revvity	RCV000211688	SCV002022671	pathogenic	Hypercholesterolemia, familial, 1	2022-09-26	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001256967	SCV002502806	likely pathogenic	not provided	2021-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390310	SCV002701356	pathogenic	Cardiovascular phenotype	2024-05-23	criteria provided, single submitter	clinical testing	The p.G478R pathogenic mutation (also known as c.1432G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1432. The glycine at codon 478 is replaced by arginine, an amino acid with dissimilar properties. This variant (also described as legacy p.G457R) has been described in several patients with familial hypercholesterolemia (FH) (Koivisto UM et al. Am J Hum Genet. 1995;57:789-97; Mak YT et al. Arterioscler Thromb Vasc Biol. 1998;18:1600-5; Bourbon M et al. Atherosclerosis. 2008;196:633-42; Chiou KR et al. J Clin Lipidol. 2016;10(3):490-6; Tada H et al. J Clin Lipidol Dec;12:397-402.e2; Hartgers ML et al. J Clin Lipidol Dec;12:390-396.e8; Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). In an assay testing LDLR function, this variant showed a functionally abnormal result (Gra&ccedil;a R et al. JACC Basic Transl Sci, 2023 Aug;8:1010-1021). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000775069	SCV004020701	pathogenic	Familial hypercholesterolemia	2023-06-19	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1432G>A (p.Gly478Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251112 control chromosomes (gnomAD). c.1432G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Koivisto_1995, Chiou_2010, Chiou_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20538126, 28502495, 7573037). 19 ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=4), likely pathogenic (n=10) and pathogenic (n=5, including one expert panel, ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel). Based on the evidence outlined above, the variant was classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000211688	SCV004822459	pathogenic	Hypercholesterolemia, familial, 1	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 478 and alters a conserved glycine residue in the second LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 439-485) where pathogenic missense variants are found enriched (ClinVar-LDLR). This variant is also known as p.Gly457Arg in the mature protein sequence and as FH New York-2 and FH Fin-9 in the literature. Computational prediction suggests that this variant may have a 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), as well as in 10 informative meiosis from 4 unpublished families (ClinVar variation ID: 161277; accession ID: SCV002506334.1). 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 Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000775069	SCV005045749	pathogenic	Familial hypercholesterolemia	2023-01-26	criteria provided, single submitter	clinical testing	The c.1432G>A (p.Gly478Arg) variant in the LDLR gene is located on the exon 10 and is predicted to replace the glycine with arginine at codon 478 (p.Gly478Arg). The variant has been reported in more than 10 unrelated individuals affected with familial hypercholesterolemia (PMIDs: 27206935, 27680772, 32331935). Another variant disrupting the same amino acid (p.Gly478Glu) has been interpreted as likely pathogenic (ClinVar ID: 440642). The p.Gly478Arg variant has been reported in ClinVar (ID: 161277) and reviewed as a pathogenic variant by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel. This variant has been observed by different laboratories to segregate with disease in over 10 meioses of 4 families according to the ClinGen Expert Panel. This variant is rare in the general population according to gnomAD (7/251112). Computational prediction algorithms suggest a deleterious impact (REVEL score 0.985). Therefore, the c.1432G>A (p.Gly478Arg) variant of LDLR has been classified as pathogenic.
CSER _CC_NCGL, University of Washington	RCV002051670	SCV000190297	uncertain significance	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211688	SCV000268615	pathogenic	Hypercholesterolemia, familial, 1	2008-06-27	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211688	SCV000606423	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000775069	SCV002086425	likely pathogenic	Familial hypercholesterolemia	2020-09-12	no assertion criteria provided	clinical testing
Medical Laboratory Center, Huzhou Maternal and Child Health Hospital	RCV000211688	SCV004800911	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research