Submissions for variant NM_000527.5(LDLR):c.661G>A (p.Asp221Asn) (rs875989906)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211605	SCV000294860	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000211605	SCV000503198	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH / Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000211605	SCV000540748	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing	Asp221 bind structural Ca2+.
Invitae	RCV000791440	SCV000544692	pathogenic	Familial hypercholesterolemia	2020-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 221 of the LDLR protein (p.Asp221Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in eight individuals affected with familial hypercholesterolemia (PMID: 17094996, 11196104, 25962062, 1714262, 24075752). This variant is also known as c.661G>A, p.Asp200Asn in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). Different missense substitutions at this codon (p.Asp221Tyr and p.Asp221Gly) are reported to be deleterious and are found in patients affected with hypercholesterolemia or myocardial infarction (PMID: 1301956, 19318025, 23375686, 25647241, 25487149). This indicates that the aspartic acid residue is important for LDLR protein function. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc	RCV000791440	SCV001358758	pathogenic	Familial hypercholesterolemia	2019-07-21	criteria provided, single submitter	clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000211605	SCV001432567	pathogenic	Familial hypercholesterolemia 1	2019-06-05	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000791440	SCV001435006	pathogenic	Familial hypercholesterolemia	2018-10-12	criteria provided, single submitter	clinical testing	The c.661G>A (p.Asp221Asn) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 9409298, 10090484, 11196104, 15199436, 15359125, 16250003, 17094996, 24075752, 25962062). The variant is not observed in gnomAD. The allelic change p.Asp221Tyr is an established pathogenic variant for FH. Functional studies demonstrated deleterious effect of the p.Asp221Asn variant. Multiple algorithms predicted this change to be deleterious. Therefore, the c.661G>A (p.Asp221Asn) variant in the LDLR gene is classified as pathogenic.
GeneDx	RCV001596987	SCV001830861	pathogenic	not provided	2020-03-31	criteria provided, single submitter	clinical testing	Located in a region intolerant to change; 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: 32719484, 31447099, 24075752, 22883975, 19837725, 15359125, 11196104, 10090484, 9544745, 16250003)
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211605	SCV000268576	pathogenic	Familial hypercholesterolemia 1	2008-06-27	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211605	SCV000606185	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research