ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1384G>A (p.Val462Ile)

gnomAD frequency: 0.00001  dbSNP: rs750363970
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238342 SCV000295408 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Color Diagnostics, LLC DBA Color Health RCV001181608 SCV001346789 uncertain significance Familial hypercholesterolemia 2023-02-17 criteria provided, single submitter clinical testing This missense variant (also known as p.Val441Ile in the mature protein) replaces valine with isoleucine at codon 462 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 20538126, 28502495, 28964736, 29396260, 33994402). One of these individuals also carried a pathogenic splice variant in the LDLR gene (PMID: 29396260). This variant has been identified in 14/250944 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.
Invitae RCV001181608 SCV003516794 uncertain significance Familial hypercholesterolemia 2022-06-09 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 462 of the LDLR protein (p.Val462Ile). This variant is present in population databases (rs750363970, gnomAD 0.02%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 20538126). This variant is also known as V441I. ClinVar contains an entry for this variant (Variation ID: 251824). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV000238342 SCV004820309 uncertain significance Hypercholesterolemia, familial, 1 2023-11-28 criteria provided, single submitter clinical testing This missense variant (also known as p.Val441Ile in the mature protein) replaces valine with isoleucine at codon 462 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 20538126, 28502495, 28964736, 29396260, 33994402). One of these individuals also carried a pathogenic splice variant in the LDLR gene (PMID: 29396260). This variant has been identified in 14/250944 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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