ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1836C>T (p.Ala612=) (rs143872778)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomarker Research Laboratory,Mayo Clinic RCV000210239 SCV000266318 uncertain significance Familial hypercholesterolemia 1 2015-08-31 criteria provided, single submitter research MAF =<0.3%, LDL-C >=160 mg/dL
LDLR-LOVD, British Heart Foundation RCV000210239 SCV000295690 likely benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000210239 SCV000410538 uncertain significance Familial hypercholesterolemia 1 2016-06-14 criteria provided, single submitter clinical testing The c.1836C>T (p.Ala612Ala) variant has been reported in two studies and is found in a total of eight familial hypercholesterolemia patients in a heterozygous state (Widhalm et al. 2007; Chmara et al. 2010). In silico analysis of this variant predicted no effect on consensus splice sites and overall non-pathogenicity (Chmara et al. 2010; Usifo et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00034 in the European (Non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Ala612Ala variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial hypercholesterolemia.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000456101 SCV000539509 uncertain significance not specified 2017-01-24 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: This is a silent variant in LDLR. It is classified as DM in HGMD. This variant has been reported in 7 patients with familial hypercholesterolemia in one study (Widhalm 2007). This variant is classified in ClinVar with 1 star as VUS by Mayo Clinic and as Likely Benign by British Heart Foundation. The variant has a Max MAF of 0.03% in ExAC (23 alleles) and 0.03% in gnomAD (43 alleles).
Invitae RCV000771188 SCV000556782 likely benign Familial hypercholesterolemia 2020-11-13 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000210239 SCV000583890 likely pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000456101 SCV000697212 likely benign not specified 2019-08-29 criteria provided, single submitter clinical testing Variant summary: LDLR c.1836C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools (Alamut) predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 251468 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease (0.00018 vs 0.001), allowing no conclusion about variant significance. The variant, c.1836C>T, has been reported in the literature in individuals affected with premature atherosclerosis and/or hypercholesterolaemia (Widhalm_2007, Chmara_2010). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (3x VUS, 4x Likely benign, 1x Likely pathogenic). Based on the evidence outlined above, the variant was re-classified as likely benign.
GeneDx RCV001705182 SCV000728649 likely benign not provided 2019-09-04 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22881376, 28145427, 17347910, 20145306, 32719484)
Color Health, Inc RCV000771188 SCV000903169 likely benign Familial hypercholesterolemia 2017-07-07 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000210239 SCV000606531 benign Familial hypercholesterolemia 1 no assertion criteria provided research

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