ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1637G>A (p.Gly546Asp)

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 RCV000003885 SCV000295551 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 RCV000003885 SCV000503379 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 6 , family members = 8 with co-segregation / FH-Saint-Omer, < 2% LDLR Activity / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003885 SCV000583857 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000003885 SCV000588599 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV001175478 SCV001339064 pathogenic Familial hypercholesterolemia 2020-03-16 criteria provided, single submitter clinical testing Variant summary: LDLR c.1637G>A (p.Gly546Asp) results in a non-conservative amino acid change located in one of the class B repeats (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes (gnomAD). The variant c.1637G>A (also known as FH Saint Omer and G525D) has been reported in the literature in multiple individuals (including at least one homozygote) who were affected with Familial Hypercholesterolemia (e.g. Hobbs_1992, Klancar_2015, Martin-Campos_2018). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant causes the retention of the protein in the endoplasmic reticulum, with eventual ubiquitination and degradation, predicted to result in the complete lack of the LDL receptor at the cell surface (Hobbs_1990, Zelcer_2009). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (2x) / likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000003885 SCV001370229 pathogenic Familial hypercholesterolemia 1 2019-04-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3,PP4.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000003885 SCV001432661 pathogenic Familial hypercholesterolemia 1 2019-05-11 criteria provided, single submitter research
OMIM RCV000003885 SCV000024050 pathogenic Familial hypercholesterolemia 1 1988-11-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003885 SCV000268626 pathogenic Familial hypercholesterolemia 1 2011-10-17 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003885 SCV000606473 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.