ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1359-1G>A (rs139617694)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000172962 SCV000212138 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844728 SCV000271383 pathogenic Familial hypercholesterolemia - homozygous 2015-12-23 criteria provided, single submitter clinical testing The c.1359-1G>A variant in LDLR has been reported in >80 individuals with famili al hypercholesterolemia (FH), segregated with disease in 8 affected relatives fr om 3 families (Peeters 1995, Lombarid 1995 and 2000, Garcia-Garcia 2001, Braenne 2015), and has been identified in 1/8600 European American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs139617 694). This variant occurs in the invariant region (+/- 1,2) of the splice consen sus sequence and is predicted to cause altered splicing leading to an abnormal o r absent protein. Heterozygous loss of LDLR function is an established disease m echanism in familial hypercholesterolemia. In summary, this variant meets our cr iteria to be classified as pathogenic for familial hypercholesterolemia in an au tosomal dominant manner. ACMG/AMP criteria applied: PVS1, PP1_S, PS4, PM2 (Richa rds 2015).
LDLR-LOVD, British Heart Foundation RCV000172962 SCV000295393 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000172962 SCV000484787 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 RCV000172962 SCV000503342 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 11 , family members = 2 with co-segregation / previously described in association with FH
Invitae RCV000775066 SCV000544700 pathogenic Familial hypercholesterolemia 2018-10-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 of the LDLR gene. It is expected to disrupt mRNA splicing and results in an absent or disrupted protein product. This variant is not present in population databases (rs139617694, ExAC no frequency). This variant has been reported to segregate with familial hypercholesterolemia in several families (PMID: 9254862, 25154303). It has also been observed in numerous unrelated individuals with familial hypercholesterolemia (PMID: 10735632, 11668640, 11857755, 15241806, 21382890, 21475731, 22390909). ClinVar contains an entry for this variant (Variation ID: 162499). Experimental studies have shown that this intronic change activates a cryptic acceptor splice site and leads to a deletion of seven nucleotides in exon 10 (PMID: 10090473). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000172962 SCV000583825 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000172962 SCV000607593 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color RCV000775066 SCV000909167 pathogenic Familial hypercholesterolemia 2017-07-24 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant changes a single nucleotide in intron 9 canonical splice acceptor site of the LDLR gene. This variant is predicted to cause aberrant splicing and likely results in an absent or disrupted protein product. An RNA study has shown that this variant causes a deletion of the first seven nucleotides of exon 10 due to a cryptic splice acceptor activation and is expected to cause a frameshift and premature truncation (PMID: 10090473). This variant has been reported in hundreds of individuals affected with familial hypercholesterolemia (PMID: 7616128, 9254862, 10735632, 11668640, 11857755, 15241806, 16792510, 21382890, 21475731, 25154303). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
CSER _CC_NCGL, University of Washington RCV000149884 SCV000190289 pathogenic Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000172962 SCV000268613 pathogenic Familial hypercholesterolemia 1 2014-03-17 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000172962 SCV000606409 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000172962 SCV000733821 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided clinical testing

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