ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.986G>A (p.Cys329Tyr) (rs761954844)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211666 SCV000295127 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211666 SCV000484751 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 RCV000211666 SCV000503275 likely benign Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211666 SCV000540780 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys318 and Cys329.
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211666 SCV000599354 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211666 SCV000268597 pathogenic Familial hypercholesterolemia 1 2008-11-17 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211666 SCV000606290 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV000211666 SCV001423089 likely pathogenic Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Cys329Tyr variant in LDLR has been reported in at least 25 individuals (including 17 Taiwanese, 2 Russian, 2 Chinese, 1 Filipino, and 1 Czech individuals) with Familial Hypercholesterolemia (PMID: 22353362, 9763532, 11810272, 15701167, 16205024, 27765764, 22698793), and has been identified in 0.01003% (2/19938) of East Asian chromosomes and 0.005645% (2/35428) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs761954844). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a likely benign variant, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 226344). In vitro functional studies with transfected COS cells provide some evidence that the p.Cys329Tyr variant may impact LDL receptor activity (PMID: 26608663). 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. One additional variant with a different amino acid change at the same position (p.Cys329Phe) has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 251586). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PS3_supporting, PM5_supporting, PP3 (Richards 2015).

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