ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.148G>T (p.Ala50Ser)

dbSNP: rs137853960
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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV002051650 SCV000190292 uncertain significance Hypercholesterolemia 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 Hypercholesterolemia, familial, 1 2015-08-31 criteria provided, single submitter research MAF =<0.3%
LDLR-LOVD, British Heart Foundation RCV000210234 SCV000294487 benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute, Western University RCV000210234 SCV000484686 likely benign Hypercholesterolemia, familial, 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 RCV000210234 SCV000503105 benign Hypercholesterolemia, familial, 1 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, Mass General Brigham 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 Hypercholesterolemia, familial, 1 2017-03-16 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000210234 SCV000583635 likely benign Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing ACMG Guidelines: Pathogenic (ii)
Fundacion Hipercolesterolemia Familiar RCV000210234 SCV000607422 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000776111 SCV000752432 likely benign Familial hypercholesterolemia 2024-01-29 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000776111 SCV000910984 likely benign Familial hypercholesterolemia 2017-11-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000455660 SCV000919594 likely benign not specified 2023-12-04 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 first class A repeat domain (IPR002172) 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 0.00054 in 262944 control chromosomes, predominantly at a frequency of 0.00097 within the Non-Finnish European subpopulation in the gnomAD database. However, in certain European regions the variant was found with a higher allele frequency, e.g. in the Swedish (0.0018), which is higher than estimated maximum expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.0013), suggesting that the variant might be benign. The variant, c.148G>T, has been reported in the literature in individuals affected with hypercholesterolemia, however it was also found 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, Geller_2018, Sustar_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. In a family the variant was found to not segregate with disease (Jensen_1994). In addition, co-occurrences with other pathogenic variants have been reported (e.g. LDLR c.12G>A (p.Trp4X); Tejedor_2010 and LDLR c.1033C>T (p.Gln345X) in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23064986, 22923420, 16542394, 20145306, 25487149, 24055113, 10090484, 11810272, 30333156, 7820934, 19717150, 15823280, 24507775, 15199436, 10735632, 24956927, 28145427, 20428891, 35913489). 16 other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=12) or VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Laboratory Services, Illumina RCV000210234 SCV001281756 likely benign Hypercholesterolemia, familial, 1 2018-09-07 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center RCV000210234 SCV001429403 uncertain significance Hypercholesterolemia, familial, 1 2019-02-04 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000058916 SCV001433284 uncertain significance not provided 2020-02-17 criteria provided, single submitter clinical testing
GeneDx RCV000058916 SCV001812513 likely benign not provided 2020-07-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27044878, 30333156, 7820934, 20506408, 18325082, 16542394, 15576851, 10090484, 26332594, 25487149, 25637381, 22390909, 24055113)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000058916 SCV002046748 likely benign not provided 2022-07-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV002390209 SCV002698728 likely benign Cardiovascular phenotype 2019-01-22 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 Hypercholesterolemia, familial, 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000210234 SCV000733812 benign Hypercholesterolemia, familial, 1 no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000455660 SCV001922567 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000455660 SCV001966630 benign not specified no assertion criteria provided clinical testing

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