ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser) (rs368838866)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238415 SCV000295875 likely benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000238415 SCV000540860 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000238415 SCV000607677 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000162008 SCV000697222 uncertain significance not provided 2017-06-07 criteria provided, single submitter clinical testing Variant summary: The LDLR c.2101G>A (p.Gly701Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large and broad control population from ExAC in 17/137956 control chromosomes at a frequency of 0.0001232, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in patients with hypercholesterolemia, coronary artery disease and/or myocardial infarction (Fouchier _2005, Duskova _2011, Thormaehlen_2015, Khera_2016) without strong evidence for causality. In two case-control studies, this variant was not significantly more enriched in patients with coronary artery disease and/or myocardial infarction than in controls (Thormaehlen_2015, Khera_2016). Based on LDLR uptake and complementation assay, one in vitro study has concluded that its pathogenicity or functional outcome is unclear (Thormaehlen _2015). There are conflicting reports of classification on this variant in ClinVar, likely pathogenic as well as likely benign (both in 2016). Taken together, this variant is currently classified as Variant of Unknown Significance.
Mendelics RCV000238415 SCV001140985 benign Familial hypercholesterolemia 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000162008 SCV001151671 uncertain significance not provided 2018-12-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV001181781 SCV001347005 uncertain significance Familial hypercholesterolemia 2020-12-01 criteria provided, single submitter clinical testing This missense variant (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 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). A functional study has shown this variant to cause a partial reduction in LDL uptake activity of the LDLR protein (PMID: 25647241). This variant has not shown significant association with increased LDL-C levels, coronary artery disease, or myocardial infarction (PMID: 22390909, 25647241). This variant has been identified in 25/282378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant is disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162008 SCV000189583 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238415 SCV000606599 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000238415 SCV000733828 likely benign Familial hypercholesterolemia 1 no assertion criteria provided clinical testing
Natera, Inc. RCV001181781 SCV001461327 uncertain significance Familial hypercholesterolemia 2020-09-16 no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000162008 SCV001917981 likely benign not provided no assertion criteria provided clinical testing

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