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

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211657	SCV000295992	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211657	SCV000484810	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211657	SCV000588664	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211657	SCV000607704	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000211657	SCV000748064	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Robarts Research Institute, Western University	RCV000211657	SCV000782941	likely pathogenic	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034620	SCV000820238	uncertain significance	Familial hypercholesterolemia	2023-08-16	criteria provided, single submitter	clinical testing	This variant, c.2397_2405del, results in the deletion of 3 amino acid(s) of the LDLR protein (p.Val800_Leu802del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with familial hypercholesterolemia. This variant is frequently in cis with p.Asn564His and may represent a single allele (PMID: 9143924, 9147888, 10090484, 12442279, 30795984). This variant is also known as 2393del9. ClinVar contains an entry for this variant (Variation ID: 226394). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (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	Hypercholesterolemia, familial, 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000211657	SCV002044429	pathogenic	Hypercholesterolemia, familial, 1	2021-12-07	criteria provided, single submitter	clinical testing	_x000D_This variant was found in the same patient as NM_000527.5:c.1690A>C. Criteria applied: PS3_MOD, PS4, PM2_SUP, PM4, PP4
CeGaT Center for Human Genetics Tuebingen	RCV001529505	SCV002063732	likely pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	LDLR: PM2, PM4, PS4:Moderate, PS3:Supporting
MGZ Medical Genetics Center	RCV000211657	SCV002581767	uncertain significance	Hypercholesterolemia, familial, 1	2022-08-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444850	SCV002732429	uncertain significance	Cardiovascular phenotype	2022-03-29	criteria provided, single submitter	clinical testing	The c.2397_2405delCGTCTTCCT variant (also known as p.V800_L802del) is located in coding exon 17 of the LDLR gene. This variant results from an in-frame CGTCTTCCT deletion at nucleotide positions 2397 to 2405. This results in the in-frame deletion of a at codon 800. This alteration has been reported in familial hypercholesterolemia (FH) cohorts and is often described on the same chromosome, or in cis, with the alteration, p.N564H (Alonso R et al. J Clin Lipidol Apr;10:953-961; Lombardi P et al. Clin Genet, 1996 Dec;50:525-6; Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Ebhardt M et al. Hum Mutat, 1999;13:257; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Mozas P et al. Hum Mutat, 2004 Aug;24:187; Martín-Campos JM et al. J Clin Lipidol Sep;12:1452-1462). This alteration was also detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). This amino acid position ranges from not well to poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000211657	SCV003830918	likely pathogenic	Hypercholesterolemia, familial, 1	2022-06-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001529505	SCV005201895	uncertain significance	not provided	2023-10-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Functional studies suggest p.(N564H) in cis with LDLR p.(V800_L802del) (also reported as p.(S820_N22del) due to alternate nomenclature) results in an affect on the enzyme function (PMID: 9143924, 12442279); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22390909, 30795984, 31447099, 9147888, 9143924, 12442279, 33740630, 32770674, 34456049, 32719484)
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211657	SCV000268667	pathogenic	Hypercholesterolemia, familial, 1	2012-08-01	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211657	SCV000606642	pathogenic	Hypercholesterolemia, familial, 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