ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.769C>T (p.Arg257Trp) (rs200990725)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237953 SCV000294964 likely benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237953 SCV000503232 likely benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / in association with c.1765G>A, p.Asp589Asn / Software predictions: Benign
Invitae RCV000237953 SCV000544695 uncertain significance Familial hypercholesterolemia 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 257 of the LDLR protein (p.Arg257Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs200990725, ExAC 0.07%) , and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 11462246, 11933210, 25461735, 25962062, 22353362, 20538126, 16250003, 26343872, 27206935). This variant is also known as p.Arg236Trp in the literature. This variant is reportedly found on the same allele as LDLR p.Asp589Asn (PMID: 16250003, 18325082). ClinVar contains an entry for this variant (Variation ID: 251446). Experimental studies have shown that this missense change does not show significant functional differences in LDLR activity, in contrast to established disease-causing variants (PMID: 25545329). In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237953 SCV000583738 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000237953 SCV000588517 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000237953 SCV000607499 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Robarts Research Institute,Western University RCV000237953 SCV000782953 uncertain significance Familial hypercholesterolemia 2018-01-02 criteria provided, single submitter clinical testing
Color RCV000775048 SCV000909147 uncertain significance Familial hypercholesterolemias 2018-08-14 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant (also known as p.Arg236Trp in the mature protein) is a missense variant located in the sixth LDLR type A repeat in the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Functional assays have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872). In two Chinese brothers with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29365890). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant is also observed in the general population and has been identified in 22/277252 chromosomes (17/18870 East Asian chromosomes) by the Genome Aggregation Database (gnomAD). Although functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease, available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845535 SCV000987649 uncertain significance not provided criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237953 SCV000606221 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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