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

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211626	SCV000295581	uncertain significance	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211626	SCV000322969	pathogenic	Familial hypercholesterolemia 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	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	RCV000211626	SCV000503384	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.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	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211626	SCV000607623	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000211626	SCV000748058	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV001034619	SCV000820242	uncertain significance	Familial hypercholesterolemia	2019-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with histidine at codon 564 of the LDLR protein (p.Asn564His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypercholesterolemia (PMID: 7550239, 17765246, 23054246) including many in whom it has been shown to coincide on the same chromosome (in cis) with p.Val800_Leu802del (PMID: 9147888, 9143924, 12442279, 10090484). However, presence of p.Val800_Leu802del can not be excluded from the individuals for whom only this single c.1690A>C variant was reported. This variant is also known as N543H in the literature. ClinVar contains entries for this variant (Variation ID: 3737, 226365). 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). A different missense substitution at this codon (p.Asn564Ser) has been determined to be pathogenic (PMID: 9654205, 21376320 20145306, 20538126). This suggests that the asparagine residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. 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	RCV000211626	SCV001432662	likely pathogenic	Familial hypercholesterolemia 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.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211626	SCV000268628	pathogenic	Familial hypercholesterolemia 1	2012-08-01	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211626	SCV000606484	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000211626	SCV000733825	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	clinical testing
Clinical Genetics,Academic Medical Center	RCV001699069	SCV001924671	pathogenic	not provided		no assertion criteria provided	clinical testing