ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.314-1G>A (rs879254471)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237693 SCV000294622 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237693 SCV000599326 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
Invitae RCV000237693 SCV000824886 pathogenic Familial hypercholesterolemia 2018-06-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypercholesterolemia (PMID: 9452078, 11810272) or refered for genetic testing (PMID: 22390909). This variant has been reported in an individual in the Universal Mutation Database (PMID: 9016531). ClinVar contains an entry for this variant (Variation ID: 251148). Experimental studies have shown that this intronic change leads to the in-frame skipping of exon 4, that codes for 3 functionally relevant LDLRA domains. Accordingly, expression of this variant in cultured cells cause a loss of LDLR protein expression at the cell surface level (PMID: 19208450). Deletions of these or any other LDLRA domains of LDLR have been reported in several individuals with hypercholesterolemia (PMID: 17426749, 22883975, 18718593, 23680767). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237693 SCV000606081 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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