Total submissions: 23
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000003878 | SCV000294905 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
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, |
RCV000003878 | SCV000484738 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
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, |
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 - |
RCV000003878 | SCV000583724 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory of Genetics and Molecular Cardiology, |
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, |
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, |
RCV000623885 | SCV000740416 | likely pathogenic | not provided | 2017-07-20 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
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, |
RCV000735406 | SCV000854561 | pathogenic | Aortic dissection; Carotid artery dissection; Internal carotid artery dissection; Carotid artery occlusion; Stroke | criteria provided, single submitter | clinical testing | ||
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, |
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, |
RCV000003878 | SCV000268581 | pathogenic | Familial hypercholesterolemia 1 | 2012-07-20 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000003878 | SCV000606201 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Diagnostic Laboratory, |
RCV000003878 | SCV000733815 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | clinical testing | ||
Stanford Center for Inherited Cardiovascular Disease, |
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. |