Submissions for variant NM_000527.5(LDLR):c.1546G>A (p.Gly516Ser)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211664	SCV000295490	likely benign	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	RCV000211664	SCV000503362	likely benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2/Software predictions: Benign
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211664	SCV000588584	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Robarts Research Institute, Western University	RCV000211664	SCV000782918	likely benign	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177035	SCV001341145	uncertain significance	Familial hypercholesterolemia	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Gly495Ser in the mature protein) replaces glycine with serine at codon 516 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 20809525, 22883975, 29399563, 31491741) and in an individual affected with acute coronary syndrome (PMID: 34526433). This variant has been identified in 24/282778 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.
Ambry Genetics	RCV002399777	SCV002706299	uncertain significance	Cardiovascular phenotype	2023-03-22	criteria provided, single submitter	clinical testing	The p.G516S variant (also known as c.1546G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1546. The glycine at codon 516 is replaced by serine, an amino acid with similar properties. This variant has been reported in hypercholesterolemia and early onset myocardial infarction cohorts; however, it was also detected in two controls and clinical details were limited in most cases (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Do R et al. Nature, 2015 Feb;518:102-6; Kim HN et al. Chonnam Med J, 2018 Jan;54:31-35). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001177035	SCV003031352	uncertain significance	Familial hypercholesterolemia	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 516 of the LDLR protein (p.Gly516Ser). This variant is present in population databases (rs141673997, gnomAD 0.06%). This missense change has been observed in individual(s) with familial hypercholesterolemia and myocardial infarction (PMID: 20809525, 22883975, 25487149, 29399563). ClinVar contains an entry for this variant (Variation ID: 226359). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000211664	SCV003816529	uncertain significance	Hypercholesterolemia, familial, 1	2022-12-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477712	SCV004219952	uncertain significance	not provided	2023-03-29	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00056 (14/24954 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 33303402 (2021), 31491741 (2019), 29399563 (2018), 22883975 (2012), 20809525 (2010)), early onset myocardial infarction (PMID: 25487149 (2015)), and healthy individuals (PMID: 25487149 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Mayo Clinic Laboratories, Mayo Clinic	RCV003477712	SCV004224559	uncertain significance	not provided	2022-07-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000211664	SCV004822474	uncertain significance	Hypercholesterolemia, familial, 1	2024-01-11	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Gly495Ser in the mature protein) is located in LDLR type B repeat 3 of EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a few individuals affected with familial hypercholesterolemia (PMID: 20809525, 22883975, 29399563). This variant has also been identified in 24/277174 chromosomes (14/24954 African chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211664	SCV000268620	uncertain significance	Hypercholesterolemia, familial, 1	2008-06-27	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211664	SCV000606451	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research