ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2260G>T (p.Gly754Trp)

dbSNP: rs559239150
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000495862 SCV000583937 likely pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000495862 SCV001423094 uncertain significance Hypercholesterolemia, familial, 1 2020-01-22 criteria provided, single submitter curation The p.Gly754Trp variant in LDLR has been reported in two individuals with probable Familial Hypercholesterolemia in ClinVar (Variation ID: 430797), and has been identified in 0.002891% (1/34588) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs559239150). 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: 430797). In summary, the clinical significance of the p.Gly754Trp variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015).
All of Us Research Program, National Institutes of Health RCV000495862 SCV004829387 uncertain significance Hypercholesterolemia, familial, 1 2023-05-16 criteria provided, single submitter clinical testing This missense variant (also known as p.Gly733Trp in the mature protein) replaces glycine with tryptophan at codon 754 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypercholesterolemia and hyperbetalipoproteinemia (ClinVar SCV000583937.1). This variant has been identified in 1/251302 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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