ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) (rs147509697)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000148577 SCV000190291 uncertain significance Hypercholesterolaemia 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Cardiovascular Biomarker Research Laboratory,Mayo Clinic RCV000211611 SCV000266321 uncertain significance Familial hypercholesterolemia 1 2016-02-19 criteria provided, single submitter research MAF =<0.3%. "Little/No effect" on the LDL receptor activity based on experimental validation.
LDLR-LOVD, British Heart Foundation RCV000211611 SCV000294427 likely benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211611 SCV000322872 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/150 normolipidemic chromosomes
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211611 SCV000540713 benign Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing A functional analysis was previously published (Pavloušková et al, 2016). This variant has no effect on LDLR protein function.
Invitae RCV000771169 SCV000556775 likely benign Familial hypercholesterolemia 2019-12-31 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000211611 SCV000607408 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000609054 SCV000697241 likely benign not specified 2020-08-31 criteria provided, single submitter clinical testing Variant summary: LDLR c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 255636 control chromosomes, predominantly at a frequency of 0.0024 within the Ashkenazi Jewish subpopulation in the gnomAD database. This frequency is approximately 2-fold the estimated maximum allele frequency expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.58G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia, however without evidence for co-segrgation with disease. In a family with Familial Hypercholesterolemia (FH), 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Medeiros_2014). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants in LDLR have also been reported in FH patients in the literature (examples- Tejedor_2011, Komarova_2013, Klancar_2015), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, showing no damaging effects by this variant (examples- Thormaehlen_2015, Pavlouskova_2016). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=5; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV000609054 SCV000730501 likely benign not specified 2017-04-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color RCV000771169 SCV000903098 likely benign Familial hypercholesterolemia 2017-05-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000211611 SCV001288138 uncertain significance Familial hypercholesterolemia 1 2018-08-16 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000609054 SCV001433283 likely benign not specified 2020-02-12 criteria provided, single submitter clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161949 SCV000189524 not provided not provided no assertion provided in vitro
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211611 SCV000268533 uncertain significance Familial hypercholesterolemia 1 2010-11-29 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211611 SCV000605999 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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