Description
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.
| # | Sample | Method | Observation |
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| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
