ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1702C>G (p.Leu568Val) (rs746959386)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237626 SCV000295587 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237626 SCV000484763 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237626 SCV000599380 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
Invitae RCV000799671 SCV000939345 pathogenic Familial hypercholesterolemias 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 568 of the LDLR protein (p.Leu568Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 26510755) and has been reported in multiple individuals with this disease (PMID: 10447263, 25962062, 18718593). This variant is also known as p.L547V in the literature. ClinVar contains an entry for this variant (Variation ID: 251976). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Leu568 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20809525), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237626 SCV000606488 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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