ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1216C>A (p.Arg406=) (rs121908043)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003944 SCV000295305 pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003944 SCV000599368 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
Integrated Genetics/Laboratory Corporation of America RCV000588218 SCV000697190 pathogenic Familial hypercholesterolemias 2017-07-10 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1216C>A (p.Arg406Arg) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing by the introduction of a cryptic splice site and ESE finder predicts that this variant may affect ESE sites at the locus. In support of these predictions, functional studies have shown that the variant splice site is used preferentially over the wild type splice site in patient cell lines and in vitro splicing assays (Tveten_Genet Test Molec Biomarkers_2009; Bourbon_Ather_2007). Additionally, the variant has been cited in numerous patients with hypercholesterolemia and segregates with disease in families (e.g., van der Graaf_Circ_2011; Du_SpringerPlus_2016; Tveten_Genet Test Molec Biomarkers_2009). This variant is absent from the large control database ExAC and control cohorts from the literature (0/120510 control chromosomes). In addition, two reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000003944 SCV000833922 pathogenic Familial hypercholesterolemia 2018-04-13 criteria provided, single submitter clinical testing This sequence change affects codon 406 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 17335829, 19371225, 17094996, 21382890, 18400033) including an individual compound heterozygous with another LDLR variant affected with autosomal recessive hypercholesterolemia (PMID: 28028493). ClinVar contains an entry for this variant (Variation ID: 3746). Experimental studies have shown that this silent change causes aberrantly spliced transcripts that are degraded via nonsense-mediated decay (PMID: 17335829, 19371225). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003944 SCV000024109 pathogenic Familial hypercholesterolemia 2008-06-01 no assertion criteria provided literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003944 SCV000606361 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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