ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.2479G>A (p.Val827Ile) (rs137853964)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148585 SCV000190299 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000030135 SCV000503493 benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 10 , family member = 1/previously described in association with FH/Software predictions: Conflicting
Color RCV000030135 SCV000689777 benign Familial hypercholesterolemia 2017-08-29 criteria provided, single submitter clinical testing
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000030135 SCV000987030 uncertain significance Familial hypercholesterolemia 2018-07-24 criteria provided, single submitter clinical testing This nucleotide substitution c.2479G>A causes an exchange of the amino acid valine for isoleucine at position 827 (p.Val827Ile). This rare variant is known in the literature as the "FH New York-5" variant and is discussed in the context of hypercholesterolemia. The pathogenicity of this gene change is assessed differently in the literature and databases and must therefore be classified as a variant of unclear clinical significance (VUS, class 3). In the first description, it was described as a disease-causing mutation and later classified as a polymorphism. This variant was found both in FH patients and in the control group. An influence of the amino acid exchange on the LDL receptor activity could not be detected so far. We observed this mutation in a patient without the classical criteria for FADH. In this case a slightly elevated TC was combined with normal LDL-C but signicantly elevated TG (up to 400 mg/dl). PMID: 1301956, 25647241, 28104544, 23680767
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000058923 SCV000189592 not provided not provided no assertion provided in vitro
GeneDx RCV000058923 SCV000521002 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing The V827I variant of uncertain significance in the LDLR gene (also reported as FH-New York 5, and as V806I due to alternate nomenclature) has been published multiple times in association with FH; however, there are conflicting reports concerning its pathogenicity (Hobbs et al., 1992; Lombardi et al., 2000; Zakharova et al., 2005; Tichý et al., 2012; Bertolini et al., 2013; Vandrovcova et al., 2013; Norsworthy et al., 2014; Durst et al., 2017). Hobbs et al. (1992) originally reported V827I in an American individual with homozygous FH, who also harbored a second variant in the LDLR gene. Lombardi et al. (2000) identified this variant in a cohort of individuals with FH from the Netherlands but did not provided detailed clinical information. The V827I variant was also identified in a 36-year-old Russian female with FH (LDL-C 321 mg/dl) (Zakharova et al., 2005). Vandrocova et al. (2013) identified V827I in a middle-aged proband with elevated total cholesterol (7.9 mmol/l), but also in the proband's adult daughter with normal cholesterol levels (4.6 mmol/l). More recently, V827I was found in 8 Israeli individuals (7 heterozygotes and 1 compound heterozygote) with a mean cholesterol level of 5.4 mmol/L (Durst et al., 2017). Study participants were also genotyped for 6 common LDL-C raising SNPs, and 6/8 V827I carriers had a 6-SNP score above the top quartile cutoff, suggesting that V827I alone is not sufficient to cause the full FH phenotype (Durst et al., 2017). Via whole exome sequencing, Do et al. (2015) identified V827I in 4 patients experiencing myocardial infarction (MI) at an early age, as well as in 5 control individuals with no history of MI. The V827I variant is observed in approximately 169/10,152 alleles (1.6%) from individuals of Ashkenazi Jewish ancestry, indicating it may be a rare benign variant in this population. The V827I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
GenomeConnect, ClinGen RCV000030135 SCV000840216 not provided Familial hypercholesterolemia no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America RCV000030135 SCV000052790 uncertain significance Familial hypercholesterolemia 2015-10-29 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000058923 SCV000697231 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing
Invitae RCV000030135 SCV000556789 likely benign Familial hypercholesterolemia 2017-10-30 criteria provided, single submitter clinical testing
LDLR-LOVD, British Heart Foundation RCV000030135 SCV000296021 likely benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000030135 SCV000606661 benign Familial hypercholesterolemia no assertion criteria provided research
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000030135 SCV000588668 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000030135 SCV000540872 uncertain significance Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing Probably not pathogenic - position 827 in NPXY signal is variable - PMID: 1968060
Phosphorus, Inc. RCV000030135 SCV000679811 uncertain significance Familial hypercholesterolemia 2017-08-01 criteria provided, single submitter clinical testing
Robarts Research Institute,Western University RCV000030135 SCV000484685 likely benign Familial hypercholesterolemia 2019-08-22 criteria provided, single submitter clinical testing
SNPedia RCV000058923 SCV000090444 not provided not provided no assertion provided not provided
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000030135 SCV000583958 likely pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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