ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.718G>A (p.Glu240Lys) (rs768563000)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182341 SCV000234645 pathogenic not provided 2017-08-20 criteria provided, single submitter clinical testing The E240K pathogenic variant in the LDLR gene (also reported as E219K and FH Charlotte due to alternate nomenclature) has been reported in several unrelated individuals with FH (Hobbs et al., 1992; Voevoda et al., 2008; Bertolini et al., 2013; Mollaki et al., 2014; Xiang et al., 2017). Furthermore, the E240K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The E240K variant is located in the LDL-receptor class A6 domain and 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. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies show that an individual who harbors the E240K variant as well as a different benign variant in the LDLR gene exhibits receptor activity 15-30% of wild type receptor activity (Hobbs et al., 1992).
LDLR-LOVD, British Heart Foundation RCV000211564 SCV000294938 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211564 SCV000503229 likely benign Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH / Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211564 SCV000583731 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586018 SCV000697249 pathogenic Familial hypercholesterolemia 2016-06-28 criteria provided, single submitter clinical testing Variant summary: The LDLR c.718G>A (p.Glu240Lys) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and acidic Glutamic acid (E) with a large size and basic Lysine (K) located in the ligand binding domain of LDLR. 3/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 2/121994 control chromosomes at a frequency of 0.0000164, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). It was reported in several FH patients indicating its pathogenicity. Additionally a functional study of LDLR function in fibroblast monolayers revealed the variant to only have the WT 15-30% LDL receptor activity suggesting the variant to be a partially transport defective allele that impairs transport between ER and Golgi. Furthermore, the variat was found not to fold into a unique disulphide bond structure like the WT does, thus leading to the conclusion that this variant gives rise to a protein folding defect. Moreover, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Robarts Research Institute,Western University RCV000211564 SCV000782952 uncertain significance Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000182341 SCV000888167 pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing
Color RCV000586018 SCV000909146 likely pathogenic Familial hypercholesterolemia 2020-04-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826173 SCV000967712 likely pathogenic Homozygous familial hypercholesterolemia 2019-03-03 criteria provided, single submitter clinical testing The p.Glu240Lys variant in LDLR (also described as p.Gly219Lys in the literature) has been reported in 6 individuals with familial hypercholesterolemia (FH) and segregated with disease in 3 affected relatives from two families (Fouchier 2005, Bertolini 2013, Hobbs 1992, Mollaki 2014, Norsworthy 2014). However, this variant has also been reported in one individual with normal cholesterol levels (Abul-Husn 2016), suggesting reduced penetrance. In vitro functional studies provide some evidence that the p.Glu240Lys variant may impact protein folding and transport of the mature protein from the ER to the Golgi (Hobbs 1992, North 2000, North 2001). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 200920) and has been identified in 7/126728 European chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP 7685633000). This frequency is consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu240Lys variant is likely pathogenic. The ACMG/AMP Criteria applied: PM2; PS3_Supporting; PS4_Moderate; PP1.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000211564 SCV001432576 pathogenic Familial hypercholesterolemia 1 2018-12-06 criteria provided, single submitter research
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000586018 SCV001443701 pathogenic Familial hypercholesterolemia 2020-04-13 criteria provided, single submitter clinical testing This variant, also known as (p.Glu219Lys) or FH Charlotte in the literature, has been previously reported as a heterozygous change in multiple unrelated individuals with Familial Hypercholesterolemia (PMID: 1301956, 16250003, 23375686). Functional studies demonstrate that this variant exhibits reduced receptor activity and impaired protein folding (PMID: 1301956, 11052664, 10704205). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0032% (9/282892) and thus is presumed to be rare. The c.718G>A (p.Glu240Lys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.718G>A (p.Glu240Lys) variant is classified as Pathogenic.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211564 SCV000268584 pathogenic Familial hypercholesterolemia 1 2012-03-01 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211564 SCV000606209 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV000211564 SCV001423087 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Glu240Lys variant in LDLR has been reported in 7 individuals with Familial Hypercholesterolemia, segregated with disease in 4 affected relatives from 2 families (PMID: 16250003, 25463123, 24956927), and has been identified in 0.005418% (7/129192) of European (non-Finnish) chromosomes, 0.005012% (1/19954) of East Asian chromosomes, and 0.004005% (1/24968) of African chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs768563000). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a likely benign variant, VUS, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 200920). In vitro functional studies with protein imaging provide some evidence that the p.Glu240Lys variant may slightly impact protein folding (PMID: 10704205). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_supporting, PP3, PP1, PS4_Supporting (Richards 2015).

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