ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.2096C>T (p.Pro699Leu) (rs201573863)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 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
Color RCV000589820 SCV000911498 likely pathogenic Familial hypercholesterolemias 2018-08-05 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as p.Pro678Leu in the mature protein) is located in the EGF-like repeat C of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Functional assays have demonstrated that the misfolded mutant protein is retained in the endoplasmic reticulum (PMID: 20089850). This variant has been reported in many African and European individuals affected with familial hypercholesterolemia (PMID: 27824480, 26892515, 23375686, 23064986, 21642693, 11851376). It has been identified in 11/276836 chromosomes (9/24032 African chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Fundacion Hipercolesterolemia Familiar RCV000237906 SCV000607675 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000589820 SCV000697211 pathogenic Familial hypercholesterolemias 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.
Invitae RCV000589820 SCV000544654 likely pathogenic Familial hypercholesterolemias 2018-11-01 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.
LDLR-LOVD, British Heart Foundation RCV000237906 SCV000295871 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237906 SCV000606597 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826172 SCV000967711 likely pathogenic Familial hypercholesterolemia - homozygous 2018-02-03 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 famili al hypercholesterolemia (FH) and 7 individuals with suspected FH (Thiart 2000, F ouchier 2001, Van Gaal 2001, Huijgen 2011, Tichy 2012, Bertolini 2013, Jannes 20 15, Wang 2016, Sharif 2016). It was also identified in 1 individual with homozyg ous FH who had a second pathogenic loss of function variant in LDLR (Schuster 19 95). This variant was also present in this individual's father who had normal ch olesterol levels, suggesting reduced penetrance. The p.Pro699Leu variant has bee n reported by other clinical laboratories in ClinVar (Variation ID# 252219) and has been identified in 9/24032 African chromosomes by the Genome Aggregation Dat abase (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs201573863). This freque ncy is low enough to be consistent with the frequency of FH in the general popul ation. Computational prediction tools and conservation analysis suggest that the p.Pro699Leu variant may impact the protein. In summary, although additional stu dies are required to fully establish its clinical significance, the p.Pro699Leu variant is likely pathogenic. ACMG/AMP Criteria applied (Richards 2015): PS4, PM 2_supporting, PP3.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000237906 SCV000588634 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237906 SCV000540843 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
Robarts Research Institute,Western University RCV000237906 SCV000484739 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237906 SCV000583929 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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