ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.185C>T (p.Thr62Met) (rs376207800)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148579 SCV000190293 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211598 SCV000268536 uncertain significance Familial hypercholesterolemia 2015-05-08 no assertion criteria provided clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211598 SCV000322877 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211598 SCV000503106 likely benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging
Color RCV000775024 SCV000909121 uncertain significance Familial hypercholesterolemias 2018-10-19 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Thr41Met in the mature protein) is located in the LDLR type A repeat 1 of the ligand binding 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. An experimental functional study has shown that this variant does not disrupt LDL uptake in cell-based assays (PMID: 25647241). This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 16250003, 18325082, 19318025, 19446849, 23375686, 25606447, 26892515), as well as in control individuals (PMID: 25487149, 25647241). This variant has also been identified in 30/276594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161951 SCV000189526 not provided not provided no assertion provided in vitro
Fundacion Hipercolesterolemia Familiar RCV000211598 SCV000607423 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000211598 SCV000285020 uncertain significance Familial hypercholesterolemia 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 62 of the LDLR protein (p.Thr62Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs376207800, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 16250003, 19717150, 25606447, 19446849, 26892515). This variant is also known as p.Thr41Met in the literature. ClinVar contains an entry for this variant (Variation ID: 161273). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
LDLR-LOVD, British Heart Foundation RCV000211598 SCV000294497 uncertain significance Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211598 SCV000606034 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454406 SCV000539515 uncertain significance not specified 2016-03-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Identified in equal number of cases and controls; ExAC: 3/164246 South Asian; ClinVar: 1 VUS
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000211598 SCV000588487 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research

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