Submissions for variant NM_000527.5(LDLR):c.1359-1G>A (rs139617694)

Total submissions: 13

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	Homozygous familial hypercholesterolemia	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	2019-10-14	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