ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2099A>G (p.Asp700Gly)

dbSNP: rs879255139
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237371 SCV002506377 likely pathogenic Hypercholesterolemia, familial, 1 2022-03-25 reviewed by expert panel curation The NM_000527.5(LDLR):c.2099A>G (p.Asp700Gly) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PS4_Supporting, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines ( The supporting evidence is as follows: PS3 - Level 1 assays: PMID 32015373: Heterologous cells (CHO), FACS assays - result - 35% cell surface LDLR, 60% binding and 52% uptake. ---- activity is below 70% of wild-type, so PS3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with FH criteria (CT>95th percentile, plus tendon xanthomata or pCHD in proband or 1st degree and hypercholesterolemia in family) from Spain (PMID: 11668640) and at least 1 index case with SB criteria for FH from China (PMID: 22353362), so PS4_Supporting is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.875. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met.
LDLR-LOVD, British Heart Foundation RCV000237371 SCV000295873 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000237371 SCV000607676 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV003581642 SCV004279532 pathogenic Familial hypercholesterolemia 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 700 of the LDLR protein (p.Asp700Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 33994402, 34456049). ClinVar contains an entry for this variant (Variation ID: 252220). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 32015373). This variant disrupts the p.Asp700 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15199436, 19118540, 23669246, 34869944). 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237371 SCV000606598 pathogenic Hypercholesterolemia, familial, 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.