ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile)

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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000030134 SCV002817169 benign Hypercholesterolemia, familial, 1 2022-05-24 reviewed by expert panel curation The NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BA1 - FAF = 0.008138 (0.8138%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is Met. BP4 - REVEL = 0.454, it is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) variant not on limits B) does not create AG C) variant is exonic and there 1 an AG nearby MES scores: variant cryptic = -1.90, wt cryptic = -1.77, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -1.90/-1.77 = 1.07 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.90/8.76 --- it is not above 0.9 --- BP4 is Met.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000247593 SCV000052789 benign not specified 2023-05-04 criteria provided, single submitter clinical testing Variant summary: LDLR c.2177C>T (p.Thr726Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0055 in 251244 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is benign. Twenty-one clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Institute for Integrative and Experimental Genomics, University of Luebeck RCV000030134 SCV000212141 likely benign Hypercholesterolemia, familial, 1 criteria provided, single submitter research
LDLR-LOVD, British Heart Foundation RCV000030134 SCV000295909 benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000030134 SCV000296927 benign Hypercholesterolemia, familial, 1 2015-07-20 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV000247593 SCV000304690 likely benign not specified criteria provided, single submitter clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000030134 SCV000323004 benign Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 1Hmz + 1Htz/100 normolipidemic individuals; 0/200 non-FH alleles
Cardiovascular Biomarker Research Laboratory, Mayo Clinic RCV000030134 SCV000323104 likely benign Hypercholesterolemia, familial, 1 2016-08-31 criteria provided, single submitter research does not meet required criteria. "Little/No effect" on the LDL receptor activity based on experimental validation.
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000030134 SCV000503472 benign Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 17/Software predictions: Benign
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation RCV000030134 SCV000540902 benign Hypercholesterolemia, familial, 1 2017-03-23 criteria provided, single submitter clinical testing
Invitae RCV000771082 SCV000556773 benign Familial hypercholesterolemia 2024-01-31 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000030134 SCV000588642 benign Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000030134 SCV000607682 benign Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Color Diagnostics, LLC DBA Color Health RCV000771082 SCV000689774 benign Familial hypercholesterolemia 2022-01-19 criteria provided, single submitter clinical testing
GeneDx RCV000247593 SCV000730513 benign not specified 2017-07-10 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Iberoamerican FH Network RCV000030134 SCV000748059 benign Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Robarts Research Institute, Western University RCV000030134 SCV000782936 benign Hypercholesterolemia, familial, 1 2018-01-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000162011 SCV000888164 benign not provided 2022-07-20 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000771082 SCV000902622 benign Familial hypercholesterolemia 2018-06-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000162011 SCV001151672 likely benign not provided 2023-10-01 criteria provided, single submitter clinical testing LDLR: BS2
Illumina Laboratory Services, Illumina RCV000030134 SCV001286052 benign Hypercholesterolemia, familial, 1 2018-04-10 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000162011 SCV002048044 benign not provided 2023-06-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV002426526 SCV002726703 benign Cardiovascular phenotype 2017-11-13 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162011 SCV000189586 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000030134 SCV000606613 benign Hypercholesterolemia, familial, 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000030134 SCV000733831 benign Hypercholesterolemia, familial, 1 no assertion criteria provided clinical testing
Natera, Inc. RCV000771082 SCV001453900 benign Familial hypercholesterolemia 2020-01-12 no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000247593 SCV001926111 benign not specified no assertion criteria provided clinical testing

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