ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.979C>T (p.His327Tyr) (rs747507019)

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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 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
Broad Institute Rare Disease Group,Broad Institute RCV001248905 SCV001422595 uncertain significance Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.His327Tyr variant in LDLR has been reported in at least 4 individuals with familial hypercholesterolemia (PMID: 9259195, 11810272, 15199436, 23833242), and has been identified in 0.05% (15/30610) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747507019). This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 251583). In vitro functional studies provide some evidence that the p.His327Tyr variant may slightly impact protein function (PMID: 19224862, 19001363). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PS4_supporting, PS3_supporting (Richards 2015).

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