ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1723C>T (p.Leu575Phe) (rs1205480064)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505222 SCV000599385 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Robarts Research Institute,Western University RCV000505222 SCV000782924 likely pathogenic Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001509013 SCV001715495 uncertain significance not provided 2019-12-13 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000505222 SCV001422786 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Leu575Phe variant in LDLR has been reported in at least one individual with Familial Hypercholesterolemia (PMID: 27830735), and has been identified in 0.005437% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). 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 likely pathogenic in ClinVar (Variation ID: 438324). In vitro functional studies provide some evidence that the p.Leu575Phe variant may impact protein function (PMID: 27830735, 29874871). 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: PS3_Moderate, PP3 (Richards 2015).

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