ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1618G>A (p.Ala540Thr)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001034632 SCV000285015 likely pathogenic Familial hypercholesterolemia 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 540 of the LDLR protein (p.Ala540Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (no rsID, ExAC 0.01%). This variant has been reported in the literature in multiple individuals affected with familial hypercholesterolemia (PMID: 9544745, 11196104, 15200491, 15241806, 18718593, 21376320, 23375686, 24075752, 25461735) and hyperlipidemia (PMID: 19007590). This variant is also known as A519T in the literature. ClinVar contains an entry for this variant (Variation ID: 226363). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function that has been reported in multiple familial hypercholesterolemia individuals. For these reasons, it has been classified as Likely Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000211624 SCV000295541 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211624 SCV000322966 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Robarts Research Institute,Western University RCV000211624 SCV000484729 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211624 SCV000503376 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 4 (2 homozygotes), family members 1 (1 homozygote) with co-segregation) / previously described in association with FH/Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211624 SCV000540827 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 RCV000211624 SCV000583853 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000211624 SCV000588598 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000211624 SCV000607618 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000996756 SCV001151664 likely pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001034632 SCV001339063 pathogenic Familial hypercholesterolemia 2020-03-30 criteria provided, single submitter clinical testing Variant summary: LDLR c.1618G>A (p.Ala540Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five 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 251472 control chromosomes. c.1618G>A has been reported in the literature in multiple individuals affected with Hypercholesterolemia (Sun_1998, Merino-Ibarra_2007, Bertolini_2013, Martin_2016). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000211624 SCV001432660 pathogenic Familial hypercholesterolemia 1 2019-03-10 criteria provided, single submitter research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211624 SCV000268625 pathogenic Familial hypercholesterolemia 1 2011-04-08 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211624 SCV000606468 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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