ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.392A>G (p.Asp131Gly)

gnomAD frequency: 0.00001  dbSNP: rs730882081
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Leipzig Medical Center RCV002468570 SCV002765093 pathogenic Hypercholesterolemia, familial, 1 2022-11-30 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS3, PS4_MOD, PM1, PM5, PM2_SUP, PP4
All of Us Research Program, National Institutes of Health RCV002468570 SCV004842631 uncertain significance Hypercholesterolemia, familial, 1 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 131 of the LDLR protein. This variant is also known as p.Asp110Gly in the mature protein. This variant alters a conserved aspartic acid residue in the LDLR type A repeat 3 of the ligand binding domain of the LDLR protein (a.a. 107 - 145), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A high-throughput functional study has shown that this variant causes a reduction in LDL uptake and localization within the endoplasmic reticulum (PMID: 25647241). This variant has been reported in an individual affected with familial hypercholesterolemia who experienced an early onset myocardial infarction (PMID: 25647241). It was also reported in an individual affected with coronary artery disease (PMID: 27050191) and in a second individual affected with myocardial infarction (PMID: 25487149). This variant has been identified in 2/251190 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that p.Asp131Gly may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161955 SCV000189530 not provided not provided no assertion provided in vitro

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