Submissions for variant NM_000527.4(LDLR):c.1690A>C (p.Asn564His)

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211626	SCV000295581	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211626	SCV000322969	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/208 non-FH alleles; 0/100 control subjects
Robarts Research Institute, Western University	RCV000211626	SCV000484725	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	RCV000211626	SCV000503384	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.2397_2405del, p.Val800_Leu802del & other mutations at same codon / Software predictions: Damaging
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211626	SCV000588602	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211626	SCV000607623	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000211626	SCV000748058	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034619	SCV000820242	pathogenic	Familial hypercholesterolemia	2023-08-16	criteria provided, single submitter	clinical testing	This variant disrupts the p.Asn564 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18718593, 20145306, 20538126, 21376320). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant has a mild impact on LDLR protein function. However, when expressed with p.Val800_Leu802del in the same cDNA, LDLR receptor function was greatly reduced (PMID: 9143924). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 564 of the LDLR protein (p.Asn564His). This variant is present in population databases (rs397509365, gnomAD 0.002%). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 7550239, 17765246, 23054246, 9147888, 9143924, 12442279, 10090484). This variant is frequently in cis with p.Val800_Leu802del and may represent a single allele. This variant is also known as N543H. ClinVar contains an entry for this variant (Variation ID: 226365). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211626	SCV001432662	likely pathogenic	Hypercholesterolemia, familial, 1	2019-01-27	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553638	SCV001774571	uncertain significance	not specified	2021-07-28	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1690A>C (p.Asn564His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251416 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.1690A>C (aka. N543H), 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.2397_2405delCGTCTTCCT (p.Val800_Leu802del) 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.Val800_Leu802del in the same protein, the LDLR receptor function was markedly reduced (to ~20-25% of the normal; Jensen_1996, Castillo_2002). Eight 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=2), likely pathogenic (n=2), 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	RCV000211626	SCV002044428	pathogenic	Hypercholesterolemia, familial, 1	2021-12-07	criteria provided, single submitter	clinical testing	_x000D_The variant was found in the same patient as NM_000527.5:c.2397_2405delCGTCTTCCT. Criteria applied: PS3_MOD, PS4, PM2_SUP, PM5_STR, PP3, PP4
CeGaT Center for Human Genetics Tuebingen	RCV001699069	SCV002063730	likely pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	LDLR: PM1, PM2, PM5, PS4:Moderate, PS3:Supporting
MGZ Medical Genetics Center	RCV000211626	SCV002581766	uncertain significance	Hypercholesterolemia, familial, 1	2022-08-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408915	SCV002715934	uncertain significance	Cardiovascular phenotype	2023-06-05	criteria provided, single submitter	clinical testing	The p.N564H variant (also known as c.1690A>C), located in coding exon 11 of the LDLR gene, results from an A to C substitution at nucleotide position 1690. The asparagine at codon 564 is replaced by histidine, an amino acid with similar properties. This alteration, also described in the literature as p.N543H, has been reported in familial hypercholesterolemia (FH) cohorts and is often described on the same chromosome, or in cis, with another alteration, p.V800_L802del (Górski B et al. Hum Genet, 1998 May;102:562-5; Tricot-Guerber F et al. Hum Mutat, 1995;6:87-8; Lombardi P et al. Clin Genet, 1996 Dec;50:525-6; Day IN et al. Hum Mutat, 1997;10:116-27; Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Martín-Campos JM et al. J Clin Lipidol Sep;12:1452-1462). Functional studies suggest this alteration has a mild impact on function, though the impact may be greater when expressed with p.V800_L802del (Jensen HK et al. Hum Mutat, 1997;9:437-44). 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). Another alteration at the same codon, p.N465S (c.1691A>G), has been described in association with FH (Górski B et al. Hum Genet, 1998 May;102:562-5. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence for this variant alone is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000211626	SCV003829609	likely pathogenic	Hypercholesterolemia, familial, 1	2023-02-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001699069	SCV004170077	uncertain significance	not provided	2023-10-11	criteria provided, single submitter	clinical testing	Has been as reported as p.(N646H) or p.(N543H) (due to alternate nomenclature) in individuals with familial hypercholesterolemia (FH) (Jensen et al., 1997; Futema et al., 2012; Dron et al., 2020; Benedek et al., 2021; Leren et al., 2021; Castillo et al., 2022; Marco-Benedi et al., 2022; Sustar et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Functional studies suggest p.(N564H) in cis with LDLR p.(V800_L802del) results in an affect on the enzyme function (Jensen et al., 1997; Castillo et al., 2002).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12442279, 18325082, 9147888, 22390909, 7550239, 10090484, 9259195, 15199436, 17765246, 21722902, 9143924, 27919364, 28475941, 30312929, 24987033, 26490271, 35913489, 34456049, 33955087, 33740630, 30293936, 32770674, 32719484, 27044878, 31447099, 10790219, 32041611, 23054246)
Mayo Clinic Laboratories, Mayo Clinic	RCV001699069	SCV005413317	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM2_moderate, PM5, PS3_moderate, PS4
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211626	SCV000268628	pathogenic	Hypercholesterolemia, familial, 1	2012-08-01	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211626	SCV000606484	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000211626	SCV000733825	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699069	SCV001924671	pathogenic	not provided		no assertion criteria provided	clinical testing