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

Total submissions: 16

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).
Labcorp Genetics (formerly Invitae), Labcorp	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	RCV000161951	SCV000539515	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	The p.Thr62Met (also reported as p.Thr41Met) variant in LDLR has been reported in at least 7 individuals with hypercholesterolemia, 1 individual with suspected hypercholesterolemia, 1 individual with hypertriglyceridemia, 1 individual with unspecified dyslipidemia, and 5 individuals with early myocardial infarction (MI) (Fouchier 2005 PMID: 16250003, Alonso 2009 PMID: 19318025, Guardamagna 2009 PMID: 19446849, Bertolini 2013 PMID: 23375686, Cymbron 2014 PMID: 25606447, Do 2015 PMID: 25487149, Thormaehlen 2015 PMID: 25647241, Sharifi 2016 PMID: 26892515, Sanchez-Hernandez 2019 PMID: 31153816, Dron 2020 PMID: 32041611, Gill 2021 PMID: 33303402). However, it was also observed in 4 MI-free controls in the same study (Do 2015 PMID: 25487149) and in one healthy control in another study of early-onset myocardial infarction (Khera 2019 PMID: 30586733). It has also been identified in 0.02% (3/15258) of Latine/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 161273). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant does not impact protein function (Thormaehlen 2015 PMID: 25647241, Benito-Vicente 2018 PMID: 30413722); however, these types of assays may not accurately represent biological function. In summary, the clinical significance of the p.Thr62Met variant is uncertain. ACMG/AMP Criteria applied: PP3, BS3_supporting.
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, 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.
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	2024-07-02	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). ClinVar contains an entry for this variant (Variation ID: 161273). 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