ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.148G>T (p.Ala50Ser) (rs137853960)

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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 Medical Center RCV000148578 SCV000190292 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 RCV000210234 SCV000266309 likely benign Familial hypercholesterolemia 2015-08-31 criteria provided, single submitter research MAF =<0.3%
LDLR-LOVD, British Heart Foundation RCV000210234 SCV000294487 benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000210234 SCV000484686 likely benign Familial hypercholesterolemia 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 RCV000210234 SCV000503105 benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 4 , 2 compound heterozygous / Software predictions: Benign
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455660 SCV000539514 uncertain significance not specified 2016-03-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 5 papers describe as VUS/nonpathogenic; ExAC: 0.1% (67/66532) European; ClinVar: 1 VUS
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000210234 SCV000540896 benign Familial hypercholesterolemia 2017-03-16 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000210234 SCV000583635 likely benign Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing ACMG Guidelines: Pathogenic (ii)
Fundacion Hipercolesterolemia Familiar RCV000210234 SCV000607422 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000210234 SCV000752432 likely benign Familial hypercholesterolemia 2017-11-30 criteria provided, single submitter clinical testing
Color RCV000776111 SCV000910984 likely benign Familial hypercholesterolemias 2017-11-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000455660 SCV000919594 likely benign not specified 2018-12-26 criteria provided, single submitter clinical testing Variant summary: LDLR c.148G>T (p.Ala50Ser also known as p.Ala29Ser) results in a conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat region of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 288730 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00053 vs 0.0013), allowing no conclusion about variant significance. The variant, c.148G>T, has been reported in the literature in individuals affected with Familial Hypercholesterolemia but also in controls and individuals with low LDL cholesterol (Ahmad_2012, Beaudoin_2012, Brusgaard_2006, Chmarra_2010, Do_2015, Ebhardt_1999, Fouchier_2001, Jensen_1994, Junyent_2010, Koeijvoets_2005, Lange_2014, Leren_2004, Tejedor_2010). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. In one family, the variant was found to not segregate with disease (Jensen_1994). Co-occurrences with other pathogenic variant(s) have been reported (LDLR c.12G>A, p.Trp4X), providing supporting evidence for a benign role (Tejedor_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant six times as likely benign/benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
SNPedia RCV000058916 SCV000090437 not provided not provided no assertion provided not provided
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000210234 SCV000606027 benign Familial hypercholesterolemia no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000210234 SCV000733812 benign Familial hypercholesterolemia no assertion criteria provided clinical testing

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