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
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 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.
LDLR-LOVD, British Heart Foundation RCV000238224 SCV000295124 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238224 SCV000606288 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Robarts Research Institute,Western University RCV000238224 SCV000484756 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing

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