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

dbSNP: rs875989906

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211605	SCV000294860	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing	Asp221 bind structural Ca2+.
Invitae	RCV000791440	SCV000544692	pathogenic	Familial hypercholesterolemia	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 221 of the LDLR protein (p.Asp221Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1714262, 11196104, 17094996, 24075752, 25962062). This variant is also known as c.661G>A, p.Asp200Asn. ClinVar contains an entry for this variant (Variation ID: 226331). 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 with a positive predictive value of 95%. This variant disrupts the p.Asp221 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 19318025, 23375686, 25487149, 25647241). 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.
Color Diagnostics, LLC DBA Color Health	RCV000791440	SCV001358758	pathogenic	Familial hypercholesterolemia	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp200Asn in the mature protein) replaces aspartic acid with asparagine at codon 221 in the LDLR type A repeat 5 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that this variant may disrupt LDLR protein folding due to defective calcium ion binding (PMID: 8784348, 9262405) and result in reduced LDLR activity (PMID: 9409298). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 9409298, 10090484, 11196104, 16250003, 17094996, 24075752, 25962062, 29399563, 33740630, 34456200). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants affecting the same codon (p.Asp221Gly, p.Asp221Tyr, Asp221Val) are considered to be disease-causing (ClinVar variation ID: 183092, 251356, 251357), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211605	SCV001432567	pathogenic	Hypercholesterolemia, familial, 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	2023-05-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 22883975, 31447099, 16250003, 10090484, 11196104, 15359125, 19837725, 24075752, 35913489, 9544745, 33955087, 33740630, 32719484, 34037665)
Ambry Genetics	RCV002372213	SCV002667794	likely pathogenic	Cardiovascular phenotype	2022-10-21	criteria provided, single submitter	clinical testing	The p.D221N variant (also known as c.661G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 661. The aspartic acid at codon 221 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in a number of individuals with familial hypercholesterolemia (Sun XM et al. Atherosclerosis, 1998 Jan;136:175-85; Ebhardt M et al. Hum. Mutat., 1999;13:257; Kim JH et al. Mol. Cells, 2004 Aug;18:63-70; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6). This alteration has also been reported as homozygous in a subject with tendom xanthomas and a total cholesterol of >500 mg/dL (Græsdal A et al. J Clin Lipidol Mar;6:331-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity	RCV000211605	SCV003827717	pathogenic	Hypercholesterolemia, familial, 1	2023-04-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001596987	SCV004219992	pathogenic	not provided	2023-02-20	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple in individuals with familial hypercholesterolemia (FH) (PMID: 9409298 (1997), 9544745 (1998), 11196104 (2000), 34456200 (2021)), including one homozygous individual (PMID: 17142622 (2006)). It has also been reported in an individual with autosomal dominant hypercholesterolemia (ADH) (PMID: 16250003 (2005)), as well as in an otherwise healthy individual (PMID: 32719484 (2020)). A functional study found this variant was damaging to protein function (PMID: 9409298 (1997)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211605	SCV000268576	pathogenic	Hypercholesterolemia, familial, 1	2008-06-27	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211605	SCV000606185	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000791440	SCV002086380	pathogenic	Familial hypercholesterolemia	2020-11-30	no assertion criteria provided	clinical testing