ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.2054C>T (p.Pro685Leu) (rs28942084)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844731 SCV000271386 pathogenic Familial hypercholesterolemia - homozygous 2015-12-21 criteria provided, single submitter clinical testing The p.Pro685Leu variant in LDLR, also described as p.Pro664Leu in the literature , has been reported in >40 individuals with familial hypercholesterolemia (FH), segregated with disease in >40 affected relatives from at least 4 families, and was identified in the homozygous state in at least 10 individuals with FH (Berto lini 2013, Sharifi 2016, Medeiros 2010,Rubinsztein 1992, Soutar 1989, Soutar 199 1, Thormaehlen 2015, Van Der Graaf 2011). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID 3702) and was identified i n 6/126656 European chromosomes by the Genome Aggregation Database (gnomAD, http ://; dbSNP rs28942084). However, this frequency is low enough to be consistent with the frequency of FH in the general population. In v itro functional studies provide some evidence that the p.Pro685Leu variant may i mpact protein function (Knight 1989, Rubinsztein 1992, Thormaehlen 2015). In sum mary, this variant meets criteria to be classified as pathogenic for familial hy percholesterolemia in an autosomal dominant manner based upon presence in multip le affected individuals, segregation studies, low frequency in controls and func tional evidence. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting .
LDLR-LOVD, British Heart Foundation RCV000003891 SCV000295846 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003891 SCV000322997 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/200 non-FH alleles
Robarts Research Institute,Western University RCV000003891 SCV000484689 likely pathogenic Familial hypercholesterolemia 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 RCV000003891 SCV000503454 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 25 (1 homozygote) , family members = 22 with co-segregation / previously described in association with FH/software prediction damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003891 SCV000540854 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003891 SCV000583924 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000003891 SCV000588630 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000003891 SCV000607670 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000775085 SCV000627025 pathogenic Familial hypercholesterolemias 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 685 of the LDLR protein (p.Pro685Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs28942084, ExAC 0.01%). This variant has been reported in several individuals affected with familial hypercholesterolemia and has been found to segregate with the disease in multiple families (PMID: 11031227, 15359125, 18718593, 21382890, 23155708, 23375686, 23669246, 2726768). This variant is also known as p.Pro664Leu in the literature. This variant has been reported in individuals in the Universal Mutation Database (PMID: 12124988) and has an entry in ClinVar (Variation ID: 3702). Experimental studies have shown that this missense change inhibits LDL-uptake in cultured lymphocytes (PMID: 19013141). For these reasons, this variant has been classified as Pathogenic.
Iberoamerican FH Network RCV000003891 SCV000748105 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Fulgent Genetics,Fulgent Genetics RCV000003891 SCV000894179 pathogenic Familial hypercholesterolemia 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000775085 SCV000909189 pathogenic Familial hypercholesterolemias 2017-05-16 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as p.Pro664Leu in the mature protein and as FH-Zambia) is a missense variant located in the EGF-like repeat C in 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 variant protein shows defective processing, accelerated turnover, reduced cell surface expression and impaired LDLR activity (PMID: 2920733, 3816797, 1464748, 25647241). While this variant is rare in the general population (9/277054 chromosomes in the Genome Aggregation Database (gnomAD)), it has been identified in numerous individuals diagnosed with familial hypercholesterolemia (PMID: 1464748, 1493640, 1884514, 19318025, 3816797, 7583548, 9763532, 15199436, 19446849, 20828696, 21310417, 21382890, 22390909, 23375686, 23680767, 25487149, 26343872, 26892515). It has also been shown to segregate with disease in multiple families (PMID: 1493640, 1830890, 2726768). Based on available evidence, this variant is classified as Pathogenic.
OMIM RCV000003891 SCV000024056 pathogenic Familial hypercholesterolemia 1992-12-01 no assertion criteria provided literature only
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162007 SCV000189582 not provided not provided no assertion provided in vitro
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003891 SCV000268656 pathogenic Familial hypercholesterolemia 2010-04-13 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003891 SCV000606588 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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