ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.2548-19G>A

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000497142 SCV000588673 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color RCV000497142 SCV000689778 likely benign Familial hypercholesterolemia 1 2017-09-17 criteria provided, single submitter clinical testing
GeneDx RCV000615749 SCV000719288 likely benign not specified 2017-05-11 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000615749 SCV001338114 likely benign not specified 2020-01-27 criteria provided, single submitter clinical testing Variant summary: LDLR c.2548-19G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 251390 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease phenotype (0.001), suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.2548-19G>A in individuals affected with Early Onset Coronary Artery Disease and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=2) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

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