ClinVar Miner

Submissions for variant NM_000527.4(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 2015-08-31 criteria provided, single submitter research MAF =<0.3%, LDL-C >=160 mg/dL
Color RCV000771188 SCV000903169 likely benign Familial hypercholesterolemias 2017-07-07 criteria provided, single submitter clinical testing
GeneDx RCV000456101 SCV000728649 likely benign not specified 2017-06-27 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.
Illumina Clinical Services Laboratory,Illumina RCV000210239 SCV000410538 uncertain significance Familial hypercholesterolemia 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.
Integrated Genetics/Laboratory Corporation of America RCV000586569 SCV000697212 uncertain significance not provided 2016-02-29 criteria provided, single submitter clinical testing Variant summary: The c.1836C>T in LDLR gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.021%. The observed frequency does not exceed the maximum expected allele frequency for a pathogenic LDLR variant of 0.1%, suggesting that it is not a common polymorphism. In addtion, it is unknown whether the control population was cardiographically evaluated or profiled for lipid levels. Therefore, they may or may not represent as true normal population with respect to the silent phenotypes associated with this gene. This variant was found in several affected individuals with premature atherosclerosis and/or hypercholesterolaemia but without strong evidence for casualty. Lastly, the variant of interest has not been reported by reputable databases/clinical laboratories. Taken together, this variant has been classified as a VUS-possibly benign, until more information becomes available.
Invitae RCV000210239 SCV000556782 likely benign Familial hypercholesterolemia 2016-12-25 criteria provided, single submitter clinical testing
LDLR-LOVD, British Heart Foundation RCV000210239 SCV000295690 likely benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000210239 SCV000606531 benign Familial hypercholesterolemia no assertion criteria provided research
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).
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000210239 SCV000583890 likely pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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