Total submissions: 18
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
RCV000172958 | SCV000212133 | likely pathogenic | Hypercholesterolemia, familial, 1 | criteria provided, single submitter | research | ||
Cardiovascular Biomarker Research Laboratory, |
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- |
RCV000172958 | SCV000294952 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
U4M - |
RCV000172958 | SCV000583735 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory of Genetics and Molecular Cardiology, |
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, |
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, |
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- |
RCV000172958 | SCV001737194 | uncertain significance | Hypercholesterolemia, familial, 1 | 2021-05-18 | criteria provided, single submitter | clinical testing | |
Gene |
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, |
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. |
RCV000162019 | SCV000189622 | not provided | not provided | no assertion provided | in vitro | ||
CSER _CC_NCGL, |
RCV002051654 | SCV000190275 | likely benign | Hypercholesterolemia | 2014-06-01 | no assertion criteria provided | research | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000172958 | SCV000606216 | benign | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
Natera, |
RCV001085872 | SCV001453893 | likely benign | Familial hypercholesterolemia | 2019-12-30 | no assertion criteria provided | clinical testing |