ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.661G>A (p.Asp221Asn) (rs875989906)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211605 SCV000294860 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 RCV000211605 SCV000503198 likely pathogenic 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
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211605 SCV000540748 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing Asp221 bind structural Ca2+.
Invitae RCV000791440 SCV000544692 pathogenic Familial hypercholesterolemia 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 221 of the LDLR protein (p.Asp221Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in eight individuals affected with familial hypercholesterolemia (PMID: 17094996, 11196104, 25962062, 1714262, 24075752). This variant is also known as c.661G>A, p.Asp200Asn in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Different missense substitutions at this codon (p.Asp221Tyr and p.Asp221Gly) are reported to be deleterious and are found in patients affected with hypercholesterolemia or myocardial infarction  (PMID: 1301956, 19318025, 23375686, 25647241, 25487149). This indicates that the aspartic acid residue is important for LDLR protein function. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211605 SCV000268576 pathogenic Familial hypercholesterolemia 1 2008-06-27 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211605 SCV000606185 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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