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

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003885	SCV000295551	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	RCV000003885	SCV000503379	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003885	SCV000588599	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2019-05-11	criteria provided, single submitter	research
Invitae	RCV001175478	SCV002175811	pathogenic	Familial hypercholesterolemia	2021-01-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly546 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17539906, 22859806). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this variant affects LDLR protein function (PMID: 2088165). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 29399563, 2088165, 31345425, 30293936, 11810272, 29974534, 25461735, 24075752, Invitae). ClinVar contains an entry for this variant (Variation ID: 3697). This variant is also described as G525D or FH Saint Omer in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 546 of the LDLR protein (p.Gly546Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid.
OMIM	RCV000003885	SCV000024050	pathogenic	Hypercholesterolemia, familial, 1	1988-11-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003885	SCV000268626	pathogenic	Hypercholesterolemia, familial, 1	2011-10-17	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003885	SCV000606473	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research