ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.185C>T (p.Thr62Met)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000211598 SCV001960949 uncertain significance Hypercholesterolemia, familial, 1 2021-06-23 reviewed by expert panel curation The NM_000527.5(LDLR):c.185C>T (p.Thr62Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - variant segregates with FH phenotype in 3 informative meiosis in 2 families from different labs (Laboratory of Genetics and Molecular Cardiology and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).
Invitae RCV000775024 SCV000285020 uncertain significance Familial hypercholesterolemia 2022-07-26 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 62 of the LDLR protein (p.Thr62Met). This variant is present in population databases (rs376207800, gnomAD 0.02%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 16250003, 19446849, 19717150, 25606447, 26892515, 33303402). This variant is also known as p.Thr41Met. ClinVar contains an entry for this variant (Variation ID: 161273). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
LDLR-LOVD, British Heart Foundation RCV000211598 SCV000294497 uncertain significance Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter research
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211598 SCV000322877 uncertain significance Hypercholesterolemia, familial, 1 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 Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging
Laboratory for Molecular Medicine, Mass General Brigham 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 Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000211598 SCV000607423 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Color Diagnostics, LLC DBA Color Health RCV000775024 SCV000909121 likely benign Familial hypercholesterolemia 2022-10-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV002408657 SCV002722204 uncertain significance Cardiovascular phenotype 2022-12-06 criteria provided, single submitter clinical testing The p.T62M variant (also known as c.185C>T), located in coding exon 2 of the LDLR gene, results from a C to T substitution at nucleotide position 185. The threonine at codon 62 is replaced by methionine, an amino acid with similar properties. This variant has been reported in hypercholesterolemia cohorts but limited clinical information was provided (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Leigh SE et al. Ann. Hum. Genet., 2008 Jul;72:485-98; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). This variant has also been detected in exome cohorts and healthy controls with limited cardiovascular history (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Do R et al. Nature, 2015 Feb;518:102-6; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89). Limited functional studies have suggested no significant impact on LDLR expression, binding, or uptake (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Benito-Vicente A et al. Sci Rep, 2018 Nov;8:16614). This amino acid position is 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.
Fulgent Genetics, Fulgent Genetics RCV000211598 SCV002806748 uncertain significance Hypercholesterolemia, familial, 1 2022-02-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000454406 SCV004241787 uncertain significance not specified 2023-12-04 criteria provided, single submitter clinical testing Variant summary: LDLR c.185C>T (p.Thr62Met) 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 0.00012 in 250804 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00012 vs 0.0013), allowing no conclusion about variant significance. c.185C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Fouchier_2005, Guardamagna_2009, Junyent_2010, Cymbron_2014, Sharifi_2016, Gill_2020). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Functional studies report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Thormaehlen_2015, Benito-Vicente_2018, Graca_2020). The following publications have been ascertained in the context of this evaluation (PMID: 30413722, 25606447, 16250003, 33303402, 35568682, 19446849, 19717150, 34456049, 26892515, 25647241). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=11) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161951 SCV000189526 not provided not provided no assertion provided in vitro
CSER _CC_NCGL, University of Washington RCV002051666 SCV000190293 uncertain significance Hypercholesterolemia 2014-06-01 no assertion criteria provided research
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211598 SCV000268536 uncertain significance Hypercholesterolemia, familial, 1 2015-05-08 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000211598 SCV000606034 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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