Total submissions: 27
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Institute for Integrative and Experimental Genomics, |
RCV000172964 | SCV000212140 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | research | ||
Laboratory for Molecular Medicine, |
RCV000844730 | SCV000271385 | pathogenic | Homozygous familial hypercholesterolemia | 2015-11-17 | 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 affec ted relatives from >3 families (Gorski 1998, Miltiadous 2001, Kuhrova 2002, Kubl aska 2008, Bourbon 2008, Chmara 2010, Diakou 2011, Tichy 2012, Bertolini 2013, D o 2015, Medeiros 2015, Jannes 2015, Braenne 2015). This variant has also been id entified in 15/126710 European chromosomes by the Genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org; dbSNP rs137929307). However, this frequ ency is low enough to be consistent with the frequency of FH in the general popu lation. Furthermore, in vitro functional studies provide some evidence that the p.Gly592Glu variant may impact protein function (Romano 2011). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholeste rolemia in an autosomal dominant manner based upon presence in multiple affected individuals and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong . |
LDLR- |
RCV000172964 | SCV000295649 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
RCV000172964 | SCV000322975 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | 0/220 non-FH alleles; 0/77 healthy control individuals |
Robarts Research Institute, |
RCV000172964 | SCV000484718 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
RCV000172964 | SCV000503412 | likely pathogenic | Familial hypercholesterolemia 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, |
RCV000172964 | SCV000540837 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000587007 | SCV000544669 | pathogenic | Familial hypercholesterolemia | 2020-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with glutamic acid at codon 592 of the LDLR protein (p.Gly592Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs137929307, ExAC 0.009%). This variant is clearly defined as a familial hypercholesterolemia causative allele (PMID: 15864114,20663204, 21310417), and is a common cause of familial hypercholesterolemia in individuals of European ancestry (PMID: 26238499, 23375686, 21925044), This variant is also known as p.Gly571Glu in the literature. ClinVar contains an entry for this variant (Variation ID: 161271). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV000162001 | SCV000582282 | pathogenic | not provided | 2018-05-04 | criteria provided, single submitter | clinical testing | The G592E variant in the LDLR gene, previously reported as G571E due to alternate nomenclature, has been reported many times in association with heterozygous FH and homozygous FH (Hobbs et al., 1992; Chmara et al., 2010; Goldman et al., 2010; Bertolini et al., 2013; Mollaki et al., 2014; Braenne et al., 2016; Gabcova et al., 2017). The G592E variant is observed in 15/126,710 (0.01%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The G592E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies demonstrate that this variant would lead to deficient LDLR protein (Susan-Resiga et al., 2017). |
U4M - |
RCV000172964 | SCV000583883 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory of Genetics and Molecular Cardiology, |
RCV000172964 | SCV000588605 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Fundacion Hipercolesterolemia Familiar | RCV000172964 | SCV000607638 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Integrated Genetics/Laboratory Corporation of America | 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 | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Hudson |
RCV000172964 | SCV000778604 | pathogenic | Familial hypercholesterolemia 1 | 2018-02-27 | criteria provided, single submitter | research | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000162001 | SCV000888163 | pathogenic | not provided | 2018-08-24 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000172964 | SCV000894177 | pathogenic | Familial hypercholesterolemia 1 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Color | RCV000587007 | SCV000903573 | pathogenic | Familial hypercholesterolemia | 2020-03-05 | criteria provided, single submitter | clinical testing | |
Department of Human Genetics, |
RCV000172964 | SCV000987017 | pathogenic | Familial hypercholesterolemia 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, |
RCV000172964 | SCV000998546 | pathogenic | Familial hypercholesterolemia 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, |
RCV000172964 | SCV001429254 | pathogenic | Familial hypercholesterolemia 1 | 2019-11-07 | criteria provided, single submitter | clinical testing | |
Brunham Lab, |
RCV000172964 | SCV001432593 | pathogenic | Familial hypercholesterolemia 1 | 2019-03-03 | criteria provided, single submitter | research | |
Dept. |
RCV000162001 | SCV000189576 | not provided | not provided | no assertion provided | in vitro | ||
CSER _CC_NCGL, |
RCV000148576 | SCV000190290 | pathogenic | Hypercholesterolaemia | 2014-06-01 | no assertion criteria provided | research | |
Cardiovascular Genetics Laboratory, |
RCV000172964 | SCV000268637 | pathogenic | Familial hypercholesterolemia 1 | 2010-09-07 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000172964 | SCV000606511 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Diagnostic Laboratory, |
RCV000172964 | SCV000733827 | likely pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | clinical testing |