ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) (rs749038326)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238573 SCV000294569 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000238573 SCV000484708 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 RCV000238573 SCV000503122 likely benign Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family members = 2 with co-segregation / other mutations at same codon / Software predictions: Damaging
GeneDx RCV000494304 SCV000582689 pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing The D90N variant in the LDLR gene has been reported previously in association with familial hypercholesterolemia (for examples, see Chang et al., 2003; Norsworthy et al., 2014; Xiang et al., 2017). Functional studies show D90N decreases LDLR on the cell surface and decreases LDL binding and internalization (Chang et al., 2003). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D90N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and is located in the LDL-receptor class A 2 domain (Uniprot). Missense variants at the same residue (D90Y, D90G, D90A, c.270T>A and c.270T>G D90E) have been reported in association with familial hypercholesterolemia, supporting the functional importance of this region of the protein (Hobbs et al., 1992; Rubinsztein et al., 1993; Marduel et al., 2010; Kolansky et al., 2008; Gabcova et al., 2016). Based on the ACMG recommendations, D90N is interpreted as a known pathogenic sequence change.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238573 SCV000583645 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238573 SCV000599321 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Invitae RCV000776467 SCV000816377 pathogenic Familial hypercholesterolemia 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 90 of the LDLR protein (p.Asp90Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs749038326, ExAC 0.07%). This variant has been reported in many individuals affected with familial hypercholesterolemia (PMID: 23375686, 16343504, 27206935, 25962062, 21376320, 12436241, 27765764, 15823276, 9763532, 12837857, 9259195, 22390909). This variant is also known as p.Asp69Asn in the literature. ClinVar contains an entry for this variant (Variation ID: 251105). Experimental studies have shown that this missense change affects LDLR subcellular localization and reduces LDLR activity (PMID: 12837857). Several different missense substitutions at this codon (p.Asp90Gly, p.Asp90Ala, p.Asp90Tyr) have been reported in individuals with familial hypercholesterolemia (PMID: 1301956, 19026292, 8347689). This suggests that the aspartic acid residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Color RCV000776467 SCV000912016 likely pathogenic Familial hypercholesterolemia 2019-11-15 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000238573 SCV001432642 pathogenic Familial hypercholesterolemia 1 2019-01-15 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238573 SCV000606056 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.