ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.682G>A (p.Glu228Lys) (rs121908029)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003878 SCV000294905 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003878 SCV000322911 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/100 Chinese normolipidemic individuals; 0/100 healthy control individuals
Robarts Research Institute,Western University RCV000003878 SCV000484738 likely pathogenic Familial hypercholesterolemia 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 RCV000003878 SCV000503221 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 9 , family members = 3 with co-segregation / FH-Canada-3, < 2% LDLR Activity / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003878 SCV000540754 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt SDE motif. SDE bind structural Ca2+.
Invitae RCV000775232 SCV000544645 pathogenic Familial hypercholesterolemia 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 228 of the LDLR protein (p.Glu228Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (rs121908029, ExAC no frequency). This variant has been reported in numerous individuals and families affected with familial hypercholesterolemia (PMID: 2318961, 21475731, 21722902, 22390909, 23375686). This variant is also known as p.Glu207Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 3691). A different missense substitution at this codon (p.Glu228Gln) has been determined to be pathogenic (PMID: 1301956, 8882879, 16250003, 17094996). This suggests that the glutamic acid residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change causes impaired lipoprotein binding (PMID: 18677035). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003878 SCV000583724 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000003878 SCV000588511 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000003878 SCV000607494 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844738 SCV000731719 pathogenic Familial hypercholesterolemia - homozygous 2017-07-31 criteria provided, single submitter clinical testing The p.Glu228Lys variant in LDLR is a common pathogenic variant that has been rep orted in a large number of individuals across several studies (Kusters 2011, Huj gen 2012, Bertolini 2013, Leitersdorf 1990). It is one of the 12 most common LD LR variants in the Dutch (Kusters 2011). This variant has been identified in 2/1 7176 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs121908029). In vitro functional studies suppor t that the p.Glu228Lys impacts protein function (Leitersdorf 1990). In addition, several other variants at the same position (p.Glu228Gln, p.Glu228Ala, p.Glu228 Gly) have been reported with evidence supporting a disease causing role (ClinVar ID: 251393, 251394, 375796), suggesting that a change at this position is not t olerated. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon fu nctional studies, presence in multiple affected individuals, low frequency in co ntrols and pathogenicity of other variants at the same amino acid position. ACMG /AMP Criteria applied: PS4, PM5_Strong, PM2, PS3_Supporting.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000623885 SCV000740416 likely pathogenic not provided 2017-07-20 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000003878 SCV000743851 pathogenic Familial hypercholesterolemia 1 2017-07-28 criteria provided, single submitter clinical testing
Iberoamerican FH Network RCV000003878 SCV000748039 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735406 SCV000854561 pathogenic Aortic dissection; Carotid artery dissection; Internal carotid artery dissection; Carotid artery occlusion; Stroke criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000003878 SCV000894170 pathogenic Familial hypercholesterolemia 1 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000775232 SCV000909484 likely pathogenic Familial hypercholesterolemia 2018-04-23 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This variant (also known as p.Glu207Lys in the mature protein and as FH Canadian-3, FH Modena, and FH Mexico-3) is a missense variant located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein that forms a calcium binding pocket. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. In experimental studies, the mutant protein has shown normal LDL binding affinity but reduced affinity for _x0001_beta-VLDL (PMID: 18677035) and delayed processing to the mature form (PMID: 2318961). While this variant is rare in the general population (4/244390 chromosomes in the Genome Aggregation Database (gnomAD)), it has been identified in numerous individuals diagnosed with familial hypercholesterolemia (PMID: 2318961, 15359125, 21475731, 21722902, 22390909, 23375686). Based on available evidence, this variant is classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000775232 SCV000919585 pathogenic Familial hypercholesterolemia 2018-07-30 criteria provided, single submitter clinical testing Variant summary: LDLR c.682G>A (p.Glu228Lys) results in a conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 244390 control chromosomes. c.682G>A has been reported in the literature in numerous individuals affected with Familial Hypercholesterolemia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing the variant to result in impaired lipoprotein binding (Hobbs_1992). In addition, other variants at this codon have been reported as pathogenic (p.Glu228Gln, p.Glu228X). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000003878 SCV000024043 pathogenic Familial hypercholesterolemia 1 1990-04-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003878 SCV000268581 pathogenic Familial hypercholesterolemia 1 2012-07-20 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003878 SCV000606201 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000003878 SCV000733815 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000623885 SCV000925135 pathogenic not provided 2017-10-19 no assertion criteria provided provider interpretation p.Glu228Lys (c.682G>A) in exon 4 of the LDLR gene (NM_000527.4; chr19-11216264-G-A) This variant is also reported as p.Glu207Lys in the literature. SCICD Classification: pathogenic variant based on strong case data and low frequency in unselected populations. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Case data (not including our patient): over 400 individuals with FH (mostly of Dutch ancestry) have this variant. · ClinVar: 12 labs § Invitae, British Heart Foundation Study, CV Research Group, Robarts Research Institute, Centre de Génétique Moléculaire et Chromosomique, Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation, U4M - Lille University & CHRU Lille,Université Lille 2 - CHRU de Lille, Laboratory of Genetics and Molecular Cardiology,University of São Paulo, Fundacion Hipercolesterolemia Familiar, Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital, Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum: at least 34 people from 9 families. · Cases in the literature: · Leitersdorf et al 1990: Reported in 3 of 130 French-Canadian patients with heterozygous FH and in 2 of 11 homozygotes. · Kusters et al 2011: Determined that this variant is a Dutch founder variant. 437 out of 10,899 patients had this variant. · Vaca et al 2011: Identified this variant in 5 out of 59 Mexican patients with FH. · Huijgen et al 2012: the purpose of this study was to analyze previously-documented variants using in silico prediction tools. · Bertolini et al 2013: This variant was identified in 31 subjects from 16 families of Italian descent. Segregation data: reported (Bertolini et al 2013) but no large families with this variant have been studied for segregation data. Functional data: Zhao and Michaely (2008): The substitution of a lysine for a glutamine at this codon destroys an important binding site. The binding affinity of a nearby residue, E208, to a VLDL molecule is reduced when substituted (E208K). Conservation data: The glutamic acid at codon 228 is completely conserved across species. Nearby pathogenic variants at this codon or neighboring codons: Per the test report, "a different missense substitution at this codon (p.Glu228Gln) has been determined to be pathogenic (PMID: 1301956, 8882879, 16250003, 17094996). This variant has not been reviewed by our team. Population data: Highest MAF in East Asian population: 0.011%. The variant was reported online in 4 of 122,190 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 2 of 8,588 individuals of East Asian descent (MAF=0.011%), 1 of 16,777 individuals of Latino descent and 1 of 55,223 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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