Submissions for variant NM_000527.5(LDLR):c.2282C>T (p.Thr761Met)

gnomAD frequency: 0.00006  dbSNP: rs138477254

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237277	SCV000295930	uncertain significance	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	RCV000237277	SCV000503476	uncertain significance	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2/Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237277	SCV000583940	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000237277	SCV000607689	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000237277	SCV000748062	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780383	SCV000917589	uncertain significance	not specified	2018-10-01	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2282C>T (p.Thr761Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 246126 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LDLR Familial Hypercholesterolemia (4.5e-05 vs 0.0013), allowing no conclusion about variant significance. The variant, c.2282C>T, has been reported in the literature in individuals affected with Familial Hypercholesterolemia and myocardial infarction (Thormaehlen_2015, Fouchier_2005, Brusgaard_2006, Amendola_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Thormaehlen_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x4, pathogenic x1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000237277	SCV001140986	uncertain significance	Hypercholesterolemia, familial, 1	2023-06-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001186237	SCV001352607	uncertain significance	Familial hypercholesterolemia	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Thr740Met in the mature protein) replaces threonine with methionine at codon 761 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 15199436, 16250003, 16542394, 21722902), and in an individual affected with dyslipidemia (PMID: 32041611). This variant has been identified in 13/251242 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000162013	SCV001433408	uncertain significance	not provided	2020-02-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001186237	SCV003522629	uncertain significance	Familial hypercholesterolemia	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 761 of the LDLR protein (p.Thr761Met). This variant is present in population databases (rs138477254, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 15199436, 16250003, 16542394, 18325082, 20428891, 22390909, 35379577, 35913489). ClinVar contains an entry for this variant (Variation ID: 161262). 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 80%. 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.
Ambry Genetics	RCV003162605	SCV003912558	uncertain significance	Cardiovascular phenotype	2023-03-10	criteria provided, single submitter	clinical testing	The p.T761M variant (also known as c.2282C>T), located in coding exon 15 of the LDLR gene, results from a C to T substitution at nucleotide position 2282. The threonine at codon 761 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in dyslipidemia and myocardial infarction cohorts (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Lombardi MP et al. Genet Test, 2006;10:77-84; Brusgaard K et al. Clin Genet, 2006 Mar;69:277-83; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855; Dron JS et al. BMC Med Genomics, 2020 Feb;13:23). This alteration was detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 Aug;26:1235-1239). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000162013	SCV004034722	uncertain significance	not provided	2024-07-11	criteria provided, single submitter	clinical testing	Observed in multiple individuals of different ethnic backgrounds with FH; however, at least two individuals also harbored additional variants in the LDLR gene (PMID: 15199436, 16250003, 16542394, 16792510, 19318025, 20428891, 21722902, 35913489); Observed in an individual with early myocardiac infarction, but normal LDL-C levels who underwent whole exome sequencing (PMID: 25487149, 25647241); Observed in a Dutch population in which carriers of this variant were concluded to have LDL-C levels that were not significantly different from non-carriers (PMID: 20506408, 22390909); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated no change in LDL uptake in comparison to wild type LDLR protein (PMID: 25647241); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25647241, 16792510, 22390909, 25637381, 16250003, 16542394, 19318025, 21722902, 20428891, 15199436, 27044878, 32041611, 32719484, 25487149, 20506408, 35379577, 35913489, 18325082, 37409534)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000162013	SCV004219975	uncertain significance	not provided	2023-07-20	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 1722902 (2011), 16792510 (2006), 15199436 (2004), 21722902 (2011)). Additionally, the variant has been reported to co-occur with other pathogenic variants in individuals with familial hypercholesterolemia (PMIDs: 20428891 (2010), 18325082 (2008)). The frequency of this variant in the general population, 0.00018 (3/16248 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000237277	SCV004818519	uncertain significance	Hypercholesterolemia, familial, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Thr740Met in the mature protein) replaces threonine with methionine at codon 761 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 15199436, 16250003, 16542394, 21722902), and in an individual affected with dyslipidemia (PMID: 32041611). This variant has been identified in 13/251242 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.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162013	SCV000189589	not provided	not provided		no assertion provided	in vitro
CSER _CC_NCGL, University of Washington	RCV002051655	SCV000190278	likely benign	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237277	SCV000606626	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000237277	SCV000733832	likely benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001186237	SCV001461331	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000162013	SCV001925439	likely benign	not provided		no assertion criteria provided	clinical testing