Submissions for variant NM_000527.5(LDLR):c.682G>A (p.Glu228Lys)

Total submissions: 23

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	2019-08-20	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	Homozygous familial hypercholesterolemia	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	2019-03-22	criteria provided, single submitter	clinical testing
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.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000003878	SCV001432572	likely pathogenic	Familial hypercholesterolemia 1	2019-01-20	criteria provided, single submitter	research
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.