Submissions for variant NM_000527.5(LDLR):c.2397_2405del (p.Val800_Leu802del)

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211657	SCV000295992	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute,Western University	RCV000211657	SCV000484810	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	RCV000211657	SCV000503485	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 8 , family member = 1 with co-segregation / systematically associated with c.1690A>C, p.Asn564His
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211657	SCV000583949	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211657	SCV000588664	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211657	SCV000607704	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000211657	SCV000748064	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Robarts Research Institute,Western University	RCV000211657	SCV000782941	likely pathogenic	Familial hypercholesterolemia 1	2018-01-02	criteria provided, single submitter	clinical testing
Invitae	RCV001034620	SCV000820238	uncertain significance	Familial hypercholesterolemia	2019-11-08	criteria provided, single submitter	clinical testing	This variant, c.2397_2405delCGTCTTCCT, results in the deletion of 3 amino acids of the LDLR protein (p.Val800_Leu802del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported on the same chromosome (in cis) with p.Asn564His in several individuals affected with hypercholesterolemia (PMID: 9147888, 9143924, 12442279, 10090484, 30795984). This variant is also known as 2393del9 in the literature. ClinVar contains entries for this variant (Variation ID: 3737, 226394). Experimental studies have shown that this variant has a mild impact on LDLR protein function. However, when expressed with p.Asn564His in the same cDNA, LDLR receptor function was greatly reduced (PMID: 9143924). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000211657	SCV001432566	likely pathogenic	Familial hypercholesterolemia 1	2019-01-27	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553637	SCV001774570	uncertain significance	not specified	2021-07-28	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2397_2405delCGTCTTCCT (p.Val800_Leu802del) results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein. The variant allele was found at a frequency of 8e-06 in 251148 control chromosomes (i.e. 2 alleles in the European (non-Finnish) subpopulation) in the gnomAD database (v2.1 dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2397_2405delCGTCTTCCT (aka. 2393del9), has been reported in the literature in several individuals affected with Familial Hypercholesterolemia (e.g. Jensen_1996, Castillo_2002, Fouchier_2001, Umans-Eckenhausen_2002, Kusters_2011, Sjouke_2016, Martin-Campos_2018, Leren_2021), however in almost all of these cases the variant reportedly occurred together with c.1690A>C (p.Asn564His) on the same chromosome (i.e. in cis), as a complex allele. These reports therefore do not provide unequivocal conclusions about association of the variant in isolation with Familial Hypercholesterolemia. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that when this variant was expressed in isolation, it had a mild effect on LDLR function (~75-85% activity of the normal; Jensen_1996), however, when it was part of the complex allele, i.e. occurring together with p.Asn564His in the same protein, the LDLR receptor function was markedly reduced (to ~20-25% of the normal; Jensen_1996, Castillo_2002). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=1), likely pathogenic (n=4), or pathogenic (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211657	SCV000268667	pathogenic	Familial hypercholesterolemia 1	2012-08-01	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211657	SCV000606642	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529505	SCV001743075	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics,Academic Medical Center	RCV001529505	SCV001925515	pathogenic	not provided		no assertion criteria provided	clinical testing