ClinVar Miner

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

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001034632 SCV000285015 pathogenic Familial hypercholesterolemia 2020-10-24 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 (rs769370816, ExAC 0.01%). This variant has been observed in individual(s) with familial hypercholesterolemia and hyperlipidemia (PMID: 9544745, 11196104, 15200491, 15241806, 18718593, 21376320, 23375686, 24075752, 25461735, 19007590). It has also been observed to segregate with disease in related individuals. 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001449699 SCV001652954 pathogenic Homozygous familial hypercholesterolemia 2020-11-15 criteria provided, single submitter clinical testing The p.Ala540Thr variant in LDLR (also described as p.Ala519Thr in the literature) has been reported in >17 individuals with familial hypercholesterolemia (FH) or hyperlipidemia, including in one homozygote and in 1 compound heterozygote with another pathogenic variant and segregated with disease in at least 9 affected relatives from 4 families (Sun 1997 PMID: 9409298, Weiss 2000 PMID: 11196104, Mozas 2004 PMID: 15241806, Dedoussis 2004 PMID: 15200491, Leren 2004 PMID: 15199436, Civeira 2008 PMID: 19007590, Miyake 2009 PMID: 18718593, Chiou 2011 PMID: 21376320, Faiz 2013 PMID: 24075752, Bertolini 2013 PMID: 23375686, Jannes 2015 PMID: 25461735, Martin 2016 PMID: 27680772, Kellogg 2018 ( It has also been reported by other clinical laboratories in ClinVar (Variation ID:226363) and has been identified in 0.007% (2/30616) of South Asian chromosomes by gnomAD ( This frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies support an impact on protein function (Sun 1997 PMID: 9409298) and computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting.
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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