ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1335C>A (p.Asp445Glu)

gnomAD frequency: 0.00002  dbSNP: rs749780672
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237931 SCV000295374 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV001731460 SCV001982619 pathogenic not provided 2023-06-09 criteria provided, single submitter clinical testing Located in the conserved YWTD_ motif in a region that is predicted to form a beta-propeller structure (Springer, 1998); the beta propeller and three EGF-like modules constitute the EGF precursor homology domain which is is critical for ligand release and recycling of the receptor (Rudenko et al., 2002; Davis et al., 1987).; 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: 11373616, 15199436, 31587492, 7573037, 33740630, 33955087, 12459547, 3494949)
Color Diagnostics, LLC DBA Color Health RCV001804976 SCV002052641 uncertain significance Familial hypercholesterolemia 2023-11-26 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glutamic acid at codon 445 of the LDLR protein. This variant is also known as pAsp424Glu in the mature protein, and as FH-Finn-8 in the literature. This variant alters a conserved aspartic acid residue in the LDLR type B repeat 2 of the LDLR protein (a.a. 439 - 485), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. One functional study suggested this variant does not affect protein expression, folding, or intracellular trafficking (PMID: 31587492). This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 7573037, 15199436, 33740630, 35474963; DOI: 10.1093/eurheartj/ehab724.2566). This variant has been identified in 4/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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.