ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237906 SCV000295871 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237906 SCV000484739 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 RCV000237906 SCV000503463 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family members = 3 with co-segregation / previously described in association with FH/software prediction damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237906 SCV000540843 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000589820 SCV000544654 likely pathogenic Familial hypercholesterolemia 2019-09-30 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 699 of the LDLR protein (p.Pro699Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs201573863, ExAC 0.01%). This variant has been observed in numerous individuals affected with familial hypercholesterolemia (PMID: 21642693, 7489239, 23375686, 22390909, 21310417, 26892515, 25461735, 10882754, 27765764). This variant is also known as Pro678Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 252219). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237906 SCV000583929 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237906 SCV000588634 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000237906 SCV000607675 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000589820 SCV000697211 pathogenic Familial hypercholesterolemia 2016-02-26 criteria provided, single submitter clinical testing Variant summary: c.2096C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Leu. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 2/120866 control chromosomes at a frequency of 0.0000165, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0012508). This variant has been reported in multiple FH patients (including homozygous and heterozygous FH patients). Some of the families showed co-segregation of the variant with disease (Schuster _1995). Taken together, this variant was classified as a Pathogenic.
Color Health, Inc RCV000589820 SCV000911498 likely pathogenic Familial hypercholesterolemia 2019-10-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826172 SCV000967711 likely pathogenic Homozygous familial hypercholesterolemia 2019-03-26 criteria provided, single submitter clinical testing The p.Pro699Leu variant in LDLR (also reported as p.Pro678Leu in the literature) has been reported in the heterozygous state at least 11 individuals with familial hypercholesterolemia (FH) and 7 individuals with suspected FH (Thiart 2000, Fouchier 2001, Van Gaal 2001, Huijgen 2011, Tichy 2012, Bertolini 2013, Jannes 2015, Wang 2016, Sharif 2016). It was also identified in 1 individual with homozygous FH who had a second pathogenic loss of function variant in LDLR (Schuster 1995). This variant was also present in this individual's father who had normal cholesterol levels, suggesting reduced penetrance. The p.Pro699Leu variant has been reported by other clinical laboratories in ClinVar (Variation ID# 252219) and has been identified in 9/24032 African chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs201573863). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Pro699Leu variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Pro699Leu variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4, PM2_supporting, PP3.
Division of Medical Genetics, University of Washington RCV000237906 SCV001424793 pathogenic Familial hypercholesterolemia 1 2019-09-10 criteria provided, single submitter clinical testing This variant has an overall allele frequency of 0.00004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. This variant has been reported in the literature in multiple individuals and families with familial hypercholesterolemia (Schuster 1995, Thiart 2000, Fouchier 2001, Van Gaal 2001, Huijgen 2011, Tichy 2012, Bertolini 2013, Janness 2015, Sharifi 2016, Wang 2016). Thus, this variant is interpreted as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284644 SCV001470534 pathogenic not provided 2019-11-21 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237906 SCV000606597 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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