ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.757C>T (p.Arg253Trp)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000172958 SCV001960911 uncertain significance Hypercholesterolemia, familial, 1 2021-06-07 reviewed by expert panel curation The NM_000527.5(LDLR):c.757C>T (p.Arg253Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (no codes were applied) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).
Institute for Integrative and Experimental Genomics, University of Luebeck RCV000172958 SCV000212133 likely pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter research
Cardiovascular Biomarker Research Laboratory, Mayo Clinic RCV000172958 SCV000266312 uncertain significance Hypercholesterolemia, familial, 1 2016-08-31 criteria provided, single submitter research MAF =<0.3%, likely pathogenic based on the integrative in-silico score. "Little/No effect" on the LDL receptor activity based on experimental validation.
LDLR-LOVD, British Heart Foundation RCV000172958 SCV000294952 uncertain significance Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000172958 SCV000583735 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000172958 SCV000588516 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001085872 SCV001001882 likely benign Familial hypercholesterolemia 2024-01-24 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001085872 SCV001344871 uncertain significance Familial hypercholesterolemia 2023-02-01 criteria provided, single submitter clinical testing This missense variant (also known as p.Arg232Trp in the mature protein) replaces arginine with tryptophan at codon 253 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 11005141, 11462246, 11810272, 20506408, 32878475) and in an individual affected with myocardial infarction (PMID: 26036859). This variant occurs at a relatively high frequency in the general population and has been identified in 56/282892 chromosomes (26/24970 African chromosomes) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001201284 SCV001372403 uncertain significance not specified 2023-09-05 criteria provided, single submitter clinical testing Variant summary: LDLR c.757C>T (p.Arg253Trp) results in a non-conservative amino acid change located in the class A repeat (IPR002172) of 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 0.00019 in 251484 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. The frequency in general population is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00019 vs 0.0013), allowing no conclusion about variant significance. Though the variant, c.757C>T, has been reported in the literature in individuals affected with Hypercholesterolemia and/or Early Onset Coronary Artery Disease (e.g., Thiart_2000, Huijgen_2010, Huijgen_2012, Brenne_2016, Do_2015, Raal_2020, Khoo_2000), the variant was not found to co-segregate with Familial Hypercholesterolemia in at least one family (e.g., Thiart_2000), or to meet any of the three proposed criteria for association with Familial Hypercholesterolemia (e.g., Huijgen_2010, Huijgen_2012 and the Jojo Genetics database). At least one publication reports experimental evidence evaluating an impact on protein function, and these results showed no damaging effect of this variant (e.g., Thormaehlen_2015). Co-occurrence with a pathogenic variant has been reported (LDLR c.313+1G>A, Thiart_2000) in a patient with moderate levels of untreated LDL-C (10.5 mmol/L), thus this evidence does not support benign or pathogenic nature of the variant considering LDLR may have semidominant inheritance. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 26036859, 34906454, 25487149, 20506408, 22390909, 11005141, 32878475, 28145427, 10882754, 25647241). Multiple ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments (Pathogenic n=1, likely benign n=3, VUS n=8, including the ClinGen expert panel (Chora_2022)). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genome-Nilou Lab RCV000172958 SCV001737194 uncertain significance Hypercholesterolemia, familial, 1 2021-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000162019 SCV002512868 uncertain significance not provided 2022-04-29 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R232W); This variant is associated with the following publications: (PMID: 25637381, 26036859, 11462246, 11810272, 22390909, 24507775, 25487149, 27044878, 27153395, 32044282, 20506408, 11005141)
Ambry Genetics RCV002390309 SCV002668645 likely benign Cardiovascular phenotype 2021-12-15 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Fulgent Genetics, Fulgent Genetics RCV000172958 SCV002789966 uncertain significance Hypercholesterolemia, familial, 1 2021-09-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000162019 SCV004219997 uncertain significance not provided 2023-06-27 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with FH with high or elevated levels of LDL-C (PMIDs: 28220743 (2017), 28145427 (2017), 24507775 (2014), 22390909 (2012), 20506408 (2010), 20506408 (2010)), and in individuals with premature myocardial infarction (PMIDs: 26036859 (2016), 25487149 (2015)). This variant was reported to have no effect on LDL uptake, however further studies are required to determine the global effect of this variant LDLR protein function (PMID: 10882754 (2000)). The frequency of this variant in the general population, 0.001 (26/24970 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.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162019 SCV000189622 not provided not provided no assertion provided in vitro
CSER _CC_NCGL, University of Washington RCV002051654 SCV000190275 likely benign Hypercholesterolemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000172958 SCV000606216 benign Hypercholesterolemia, familial, 1 no assertion criteria provided research
Natera, Inc. RCV001085872 SCV001453893 likely benign Familial hypercholesterolemia 2019-12-30 no assertion criteria provided clinical testing

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