ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2479G>A (p.Val827Ile)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000030135 SCV000296021 likely benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000030135 SCV000484685 likely benign Familial hypercholesterolemia 1 2019-08-22 criteria provided, single submitter clinical testing
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 1 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
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.
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000030135 SCV000540872 uncertain significance Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing Probably not pathogenic - position 827 in NPXY signal is variable - PMID: 1968060
Invitae RCV001079897 SCV000556789 likely benign Familial hypercholesterolemia 2019-12-31 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000030135 SCV000583958 likely pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000030135 SCV000588668 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Phosphorus, Inc. RCV000030135 SCV000679811 uncertain significance Familial hypercholesterolemia 1 2017-08-01 criteria provided, single submitter clinical testing
Color RCV000030135 SCV000689777 benign Familial hypercholesterolemia 1 2017-08-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855648 SCV000697231 uncertain significance not specified 2019-09-09 criteria provided, single submitter clinical testing Variant summary: LDLR c.2479G>A (p.Val827Ile) results in a conservative amino acid change in 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 0.001 in 254024 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.001 vs 0.0013), allowing no conclusion about variant significance. The variant, c.2479G>A, has been reported in the literature in compound heterozygous and homozygous individuals affected with Familial Hypercholesterolemia (Hobbs_1992, Kolansky_2008, Vandrovcova_2013, Zakharova_2005, Durst_2016). The report does not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. In addition, one family reports the variant to no segregate with disease (Vandrovcova et al 2013). Co-occurrences with other pathogenic variants have been reported (LDLR c.651_653TGG, p.Gly219del; LDLR c.418G>A, p.Glu140Lys; LDLR c.420G>T, p.Glu140Asp), providing supporting evidence for a benign role. However, although FH is autosomal dominant, homozygous and compound heterozygous individuals have more severe LDL hypercholesterolaemia (>12 mmol/L) and typically xanthomata in the skin and tendons; therefore, these co-occurrences are not considered sufficient evidence for a neutral outcome. Hobb_1992 reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Ten ClinVar submissions (evaluation after 2014) cite the variant five times as uncertain significance, twice as likely benign, twice as benign, and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000030135 SCV000987030 uncertain significance Familial hypercholesterolemia 1 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000058923 SCV001134262 benign not provided 2019-05-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000030135 SCV001286499 uncertain significance Familial hypercholesterolemia 1 2017-04-27 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000030135 SCV001432640 likely pathogenic Familial hypercholesterolemia 1 2019-01-27 criteria provided, single submitter research
SNPedia RCV000058923 SCV000090444 not provided not provided no assertion provided not provided
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000058923 SCV000189592 not provided not provided no assertion provided in vitro
CSER _CC_NCGL, University of Washington RCV000148585 SCV000190299 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000030135 SCV000606661 benign Familial hypercholesterolemia 1 no assertion criteria provided research
GenomeConnect, ClinGen RCV000030135 SCV000840216 not provided Familial hypercholesterolemia 1 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.

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