ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys) (rs137943601)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV001034664 SCV000052780 pathogenic Familial hypercholesterolemia 2019-09-16 criteria provided, single submitter clinical testing Variant summary: LDLR c.1222G>A (p.Glu408Lys) results in a conservative amino acid change in 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 8e-06 in 251304 control chromosomes (gnomAD). The variant, c.1222G>A, has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Hobbs_1992, Webb_1996). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Hobbs_1992, Webb_1996). Eight ClinVar submissions (evaluation after 2014) cite the variant twice as pathogenic and six times as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001034664 SCV000285013 pathogenic Familial hypercholesterolemia 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 408 of the LDLR protein (p.Glu408Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs137943601, ExAC 0.002%). This variant has been reported in multiple unrelated individuals and families affected with hypercholesterolemia (PMID: 1301956, 14974088, 17347910, 19843101, 20236128). This variant is also known as FH Algeria-1 or E387K in the literature. ClinVar contains an entry for this variant (Variation ID: 36453). Experimental studies have shown that this missense change is a recycling-defective allele (PMID: 1301956, 21531209). In summary, this variant is rare in population databases, has been observed in many patients with hypercholesterolemia, and has been shown to have a deleterious effect on protein function. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000030125 SCV000295310 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000030125 SCV000322938 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/208 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000030125 SCV000503319 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 10 , family members = 5 with co-segregation / FH-Algérie-1/Osaka, <2% LDLR Activity / Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000030125 SCV000540803 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000030125 SCV000583809 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000030125 SCV000607577 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844747 SCV000711398 likely pathogenic Homozygous familial hypercholesterolemia 2017-12-08 criteria provided, single submitter clinical testing The p.Glu408Lys variant in LDLR (also described as p.Glu387Lys in the literature ), has been reported in one individual with early myocardial infarction (Do 2015 ) and at least 7 individuals with familial hypercholesterolemia (FH), including at least 3 heterozygotes, 3 homozygotes and 1 compound heterozygote with a secon d pathogenic variant in the LDLR gene (Hobbs 1992, Dedoussis 2004, Widhalm 2007, Taylor 2010). Other clinical laboratories have also reported this variant in Cl inVar (Variation ID 36453). In vitro functional studies provide some evidence t hat the p.Glu408Lys variant may impact ligand recycling as it failed to release ligands in the endosome (Hobbs 1992, Strom 2011). This variant has also been ide ntified in 2/111530 European chromosomes by the Genome Aggregation Database (Gno mAD, http://gnomad.broadinstitute.org; dbSNP rs137943601). This frequency is low enough to be consistent with the frequency of FH in the general population. Add itionally, other amino acid changes at this position have been reported in indiv iduals with FH (Palcoux 2008, Duscova 2011), suggesting that changes at this pos ition may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu408Lys variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_moderate, PM2, PS3_supporting, PM5_s upporting (Richards 2015).
Color RCV001034664 SCV001347901 pathogenic Familial hypercholesterolemia 2019-12-04 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000030125 SCV001429020 pathogenic Familial hypercholesterolemia 1 2019-07-23 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000030125 SCV001432552 likely pathogenic Familial hypercholesterolemia 1 2018-11-29 criteria provided, single submitter research
CSER _CC_NCGL, University of Washington RCV000148564 SCV000190277 likely benign Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000030125 SCV000268606 pathogenic Familial hypercholesterolemia 1 2011-08-25 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000030125 SCV000606366 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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