Submissions for variant NM_000527.5(LDLR):c.1646G>A (p.Gly549Asp)

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003886	SCV000295560	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute,Western University	RCV000003886	SCV000484682	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	RCV000003886	SCV000503381	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , family member = 1 with co-segregation / FH-Palermo, 2% LDLR activity / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000003886	SCV000540828	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing
Invitae	RCV000587938	SCV000544685	pathogenic	Familial hypercholesterolemia	2020-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with aspartic acid at codon 549 of the LDLR protein (p.Gly549Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs28941776, ExAC 0.009%). This variant is clearly defined as a familial hypercholesterolemia causative allele (PMID: 23375686, 25487149). It is a common cause of familial hypercholesterolemia in individuals of Italian ancestry. This variant is also known as p.Glu528Asp in the literature. ClinVar contains an entry for this variant (Variation ID: 3698). Experimental studies have shown that this missense change inhibits the transport of the LDLR protein to the cellular surface (PMID: 25647241). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003886	SCV000583858	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003886	SCV000588600	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000003886	SCV000607619	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587938	SCV000697207	pathogenic	Familial hypercholesterolemia	2017-03-17	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000003886	SCV000894176	pathogenic	Familial hypercholesterolemia 1	2018-10-31	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000587938	SCV001346737	pathogenic	Familial hypercholesterolemia	2021-02-18	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Gly528Asp in the mature protein and as FH Genoa, FH Palermo-1) is located in the fourth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). Experimental functional studies have shown that this variant causes defective LDLR protein transport (PMID: 2088165) and results in <2-5% LDLR activity (PMID: 1301956, 25647241). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 8683740, 9259195, 9544850, 11810272, 15241806, 23375686) and particularly common in Greek (PMID: 8683740) and Italian populations (PMID: 23375686). This variant has been identified in 6/246260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000003886	SCV001433282	pathogenic	Familial hypercholesterolemia 1	2020-02-11	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000587938	SCV001435010	pathogenic	Familial hypercholesterolemia	2018-08-06	criteria provided, single submitter	clinical testing	The c.1646G>A (p.Gly549Asp) variant has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID 1301956,9259195, 9544850, 11810272, 15199436, 15241806, 19837725, 21865347, 23375686) or myocardial infarction (PMID 25487149). A functional study reported the mutant LDLR protein retains less than 2 percent receptor activity compared to wild type LDLR protein (PMID 1301956) and the variant is classified as 'disruptive' through systematic cell-based phenotyping (PMID 25647241). Therefore, this c.1646G>A (p.Gly549Asp) variant is classified as pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000003886	SCV001653643	pathogenic	Familial hypercholesterolemia 1	2021-05-24	criteria provided, single submitter	clinical testing	Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.
Mayo Clinic Laboratories, Mayo Clinic	RCV000161997	SCV001715493	pathogenic	not provided	2020-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000161997	SCV001782225	pathogenic	not provided	2020-12-18	criteria provided, single submitter	clinical testing	Also reported as FH Genoa, FH Palermo-1, and G528D due to alternate nomenclature; Published functional studies demonstrate a damaging effect with abnormal LDL transport/uptake and significantly reduced receptor activity (Hobbs et al., 1990; Romano et al., 2011; Thormaehlen et al., 2015; Rodriguez-Jimenez et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#3698; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32770674, 32041611, 32977124, 31106925, 31447099, 29874871, 27578104, 25463123, 21310417, 21925044, 22371747, 19837725, 19717150, 19446849, 15241806, 15199436, 11317361, 9544850, 9259195, 2088165, 20045108, 28391899, 21865347, 25525159, 25647241, 25487149, 23375686, 28965616, 33093846)
OMIM	RCV000003886	SCV000024051	pathogenic	Familial hypercholesterolemia 1	1988-11-01	no assertion criteria provided	literature only
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161997	SCV000189572	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000003886	SCV000606474	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000003886	SCV000733824	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	clinical testing
Iberoamerican FH Network	RCV000003886	SCV000748175	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	no assertion criteria provided	research
Clinical Genetics,Academic Medical Center	RCV000161997	SCV001925125	pathogenic	not provided		no assertion criteria provided	clinical testing