Submissions for variant NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu)

Total submissions: 44

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000172964	SCV001960930	pathogenic	Hypercholesterolemia, familial, 1	2021-06-09	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PS3_Moderate, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 239 index cases. PP1_strong - 130 informative meioses (1 from Robarts Research Institute; 83 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 19 from Laboratory of Genetics and Molecular Cardiology; 2 from University of British Columbia; 25 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PM2 - PopMax MAF = 0.0001161 (0.012%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay - PMID:21865347 - study on hmz patient's lymphocytes, FACS, LDLR activity value range: 39-53%. PP3 - REVEL: 0,938. PP4 - Variant meets PM2. Variant identified in 239 index cases fulfill specific clinical criteria for FH (3 cases with Simon-Broome from Color laboratory; 189 cases with MedPed criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 5 cases with Simon-Broome criteria from GeneDx; 15 cases with Siom-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 2 cases with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 6 cases with DLCN criteria from University of British Columbia; 19 cases with Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).
Institute for Integrative and Experimental Genomics, University of Luebeck	RCV000172964	SCV000212140	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844730	SCV000271385	pathogenic	Homozygous familial hypercholesterolemia	2020-09-04	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 affected relatives from >3 families (Gorski 1998 PMID: 9654205, Miltiadous 2001 PMID: 11317361, Kuhrova 2002 PMID: 11754108, Kublaska 2008 PMID: 18263977, Bourbon 2008 PMID: 17765246, Chmara 2010 PMID: 20145306, Diakou 2011 PMID: 21925044, Tichy 2012 PMID: 22698793, Bertolini 2013 PMID: 23375686, Do 2015 PMID: 25487149, Medeiros 2015 PMID: 26020417, Jannes 2015 PMID: 25461735, Braenne 2015 PMID: 26036859). This variant has also been identified in 0.01% (15/129176) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of FH in the general population. Furthermore, in vitro functional studies support that the p.Gly592Glu variant may impact protein function (Romano 2011 PMID: 21865347). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in multiple affected individuals and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Supporting.
LDLR-LOVD, British Heart Foundation	RCV000172964	SCV000295649	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000172964	SCV000322975	likely pathogenic	Hypercholesterolemia, familial, 1	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	Hypercholesterolemia, familial, 1		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	Hypercholesterolemia, familial, 1	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	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Invitae	RCV000587007	SCV000544669	pathogenic	Familial hypercholesterolemia	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 592 of the LDLR protein (p.Gly592Glu). This variant is present in population databases (rs137929307, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15864114, 20663204, 21310417). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 21925044, 23375686, 26238499). This variant is also known as p.Gly571Glu. ClinVar contains an entry for this variant (Variation ID: 161271). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000162001	SCV000582282	pathogenic	not provided	2023-03-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that G592E results in reduced LDL receptor activity (Hobbs et al., 1992); 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 p.G571E, FH Sicily, FH Foggi, FH Naples-4; This variant is associated with the following publications: (PMID: 27998977, 11524740, 24627126, 25282520, 34167030, 32423031, 35339733, 34697415, 21310417, 15864114, 26238499, 11641914, 22390909, 25637381, 21865347, 20145306, 26036859, 20663204, 15523646, 11848618, 26666465, 27824480, 21382890, 27050191, 19062533, 27578104, 25463123, 27784735, 22294733, 22698793, 26020417, 26892515, 15890894, 23833242, 18263977, 25487149, 16627557, 25936317, 23375686, 24507775, 26723464, 28965616, 15241806, 19026292, 17539906, 9654205, 17196209, 11139254, 20506408, 11754108, 11317361, 31617323, 31447099, 21925044, 33975813, 33303402, 32719484, 32660911, 33269076, 32770674, 32977124, 31589614, 32041611, 33740630, 33418990, 34037665, 34456049, 32009526, 35741760, 35913489, 33955087, 30710474, 1301956)
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000172964	SCV000583883	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000172964	SCV000588605	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000172964	SCV000607638	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587007	SCV000697209	pathogenic	Familial hypercholesterolemia	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	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000172964	SCV000778604	pathogenic	Hypercholesterolemia, familial, 1	2018-02-27	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000162001	SCV000888163	pathogenic	not provided	2022-04-08	criteria provided, single submitter	clinical testing	Internal analysis revealed that the variant was statistically enriched in familial hypercholesterolemia cases over matched controls in the published literature (PMID: 17765246 (2008), 20145306 (2010), 21925044 (2011), 22698793 (2012), and 23375686 (2013)). Additionally, reduced LDL receptor activity was observed from fibroblasts and peripheral blood T-lymphocytes extracted from patients with this variant ((PMID: 1301956 (1992) and 21865347 (2011)).
Fulgent Genetics, Fulgent Genetics	RCV000172964	SCV000894177	pathogenic	Hypercholesterolemia, familial, 1	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000587007	SCV000903573	pathogenic	Familial hypercholesterolemia	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 592 in the fifth LDLR type B repeat of the LDLR protein. This variant is also known as p.Gly571Glu in the mature protein and as FH-Sicily, FH Foggia-1, FH Naples. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional 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, 31947532, 35741760). This variant is highly recurrent in Slovakia, Czech Republic, and Poland (PMID: 26238499). A different variant occurring at the same codon, p.Gly592Arg, is a likely pathogenic mutation (Clinvar variation ID: 373769), indicating that glycine at this position is important for LDLR protein function. This variant has been identified in 16/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000172964	SCV000987017	pathogenic	Hypercholesterolemia, familial, 1	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	Hypercholesterolemia, familial, 1		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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000172964	SCV001429254	pathogenic	Hypercholesterolemia, familial, 1	2023-08-15	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PP1_STR,PS3_MOD,PM5,PM2_SUP,PP3
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000172964	SCV001432593	pathogenic	Hypercholesterolemia, familial, 1	2019-03-03	criteria provided, single submitter	research
Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	RCV000587007	SCV001482461	likely pathogenic	Familial hypercholesterolemia		criteria provided, single submitter	research
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000172964	SCV001653652	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing	Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.
AiLife Diagnostics, AiLife Diagnostics	RCV000162001	SCV002503265	pathogenic	not provided	2022-02-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV002051664	SCV002506438	pathogenic	Hypercholesterolemia	2021-12-15	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM1,PP1,PP3,PP4,PP5
Laan Lab, Human Genetics Research Group, University of Tartu	RCV000172964	SCV002538607	pathogenic	Hypercholesterolemia, familial, 1	2021-05-01	criteria provided, single submitter	research
MGZ Medical Genetics Center	RCV000172964	SCV002580733	pathogenic	Hypercholesterolemia, familial, 1	2022-08-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399517	SCV002714823	pathogenic	Cardiovascular phenotype	2021-09-21	criteria provided, single submitter	clinical testing	The p.G592E pathogenic mutation (also known as c.1775G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1775. The glycine at codon 592 is replaced by glutamic acid, an amino acid with some similar properties, and is located in the EGF precursor-like domain. This mutation, also known as FH-Sicily and G571E, has been detected in many unrelated individuals with familial hypercholesterolemia (FH), and has also been reported to impact protein function (Hobbs et al. Hum Mutat. 1992;1(6):445-66; Miltiadous G et al. Hum Mutat. 2001;17(5):432-3; Romano M et al. J Lipid Res. 2011;52(11):2095-100; Susan-Resiga D et al. J Biol Chem. 2017;292(5):1573-1590). In addition, this mutation has been reported as one of the most common amongst Czech, Polish, German, Austrian, and Slovak FH cohorts (Chmara M et al. J Appl Genet. 2010;51(1):95-106; Tichy et al. Atherosclerosis. 2012;223(2):401-8; Gabová D et al. Physiol Res. 2017;66(1):75-84). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000172964	SCV003827125	pathogenic	Hypercholesterolemia, familial, 1	2022-11-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000172964	SCV003836115	pathogenic	Hypercholesterolemia, familial, 1	2021-12-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000162001	SCV003918065	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	LDLR: PP1:Strong, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV003330084	SCV004037152	likely pathogenic	Syndromic X-linked intellectual disability Najm type		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000162001	SCV004227680	pathogenic	not provided	2022-06-02	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PP4, PM2, PS3, PS4
All of Us Research Program, National Institutes of Health	RCV000172964	SCV004822500	pathogenic	Hypercholesterolemia, familial, 1	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Gly571Glu in the mature protein and as FH-Sicily, FH Foggia-1, FH Naples) is located in the fifth LDLR type B repeat 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). A functional 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, 31947532, 35741760). This variant is highly recurrent in Slovakia, Czech Republic, and Poland (PMID: 26238499). A different variant occurring at the same codon, p.Gly592Arg, is a likely pathogenic mutation (Clinvar variation ID: 373769), indicating that glycine at this position is important for LDLR protein function. This variant has been identified in 16/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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	RCV002051664	SCV000190290	pathogenic	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000172964	SCV000268637	pathogenic	Hypercholesterolemia, familial, 1	2010-09-07	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000172964	SCV000606511	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000162001	SCV000733827	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000587007	SCV001461319	pathogenic	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000162001	SCV001918371	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000162001	SCV001951679	pathogenic	not provided		no assertion criteria provided	clinical testing