ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.979C>T (p.His327Tyr) (rs747507019)

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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 RCV000238224 SCV000295124 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000238224 SCV000484756 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238224 SCV000503272 likely benign Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Damaging
Integrated Genetics/Laboratory Corporation of America RCV000590256 SCV000697257 uncertain significance not provided 2016-12-14 criteria provided, single submitter clinical testing Variant summary: The LDLR c.979C>T (p.His327Tyr) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant. This variant is present in 8/120554 control chromosomes, which does not exceed the max expected frequency for a pathogenic variant in this gene. The variant has been reported in affected inviduals in the literature, without strong evidence for causality, including co-occurrence data and co-segregation data. Two independent functional studies reveal that this variant results in a molecular gain-of-function, i.e. enhanced LDLR binding to PCSK9. This increased affinity of PCSK9 to the LDLR would in turn lead to enhanced LDLR destruction, decreased plasma LDL-C clearance, and hypercholesterolemia. However, due to the lack of strong clinical data, this variant can not be definitively classified as pathogenic. Taken together, this variant is classified as VUS-possibly pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238224 SCV000606288 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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