ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.420G>C (p.Glu140Asp) (rs879254520)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237168 SCV000294701 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 RCV000237168 SCV000503155 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237168 SCV000540732 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV001201387 SCV000544691 pathogenic Familial hypercholesterolemia 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 140 of the LDLR protein (p.Glu140Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypercholesterolemia (PMID: 17094996, 17094996, 20145306, 11754108). ClinVar contains an entry for this variant (Variation ID: 251216). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The p.Glu140 amino acid residue in LDLR has been determined to be clinically significant (PMID: 1301956, 11668627, 21722902, 23375686). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000237168 SCV000839978 likely pathogenic Familial hypercholesterolemia 1 2017-10-23 criteria provided, single submitter clinical testing This c.420G>C (p.Glu140Asp) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 11754108, 20145306, 22698793, 23680767). A different variant at the same residue (p.Glu140Lys) has also been described in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 11668627, 21722902, 23375686) The p.Glu140Asp variant occurs within the low-density lipoprotein receptor repeat class A domain of the LDLR protein (https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi?seqinput=NP_001182729.1 ). The c.420G>C variant is not detected in the general population and glutamate at position 140 of the LDLR protein is highly evolutionarily conserved. The c.420G>C (p.Glu140Asp) variant in the LDLR gene is classified as likely pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000237168 SCV001432649 pathogenic Familial hypercholesterolemia 1 2019-06-05 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237168 SCV000606114 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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