ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2225C>T (p.Thr742Ile)

gnomAD frequency: 0.00001  dbSNP: rs767546791
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237861 SCV000295920 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000455106 SCV000539522 uncertain significance not specified 2017-01-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Insufficient evidence for VUS5
Color Diagnostics, LLC DBA Color Health RCV001186236 SCV001352606 uncertain significance Familial hypercholesterolemia 2023-06-15 criteria provided, single submitter clinical testing This missense variant (also known as p.Thr721Ile in the mature protein) replaces threonine with isoleucine at codon 742 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 performed for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 11462246, 17142622) and in an individual affected with myocardial infarction (PMID: 34615865). This variant has been identified in 2/251326 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 RCV001186236 SCV002197455 uncertain significance Familial hypercholesterolemia 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 742 of the LDLR protein (p.Thr742Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs767546791, ExAC 0.002%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11462246, 19837725). ClinVar contains an entry for this variant (Variation ID: 252259). 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 RCV000237861 SCV004818510 uncertain significance Hypercholesterolemia, familial, 1 2024-01-11 criteria provided, single submitter clinical testing This missense variant (also known as p.Thr721Ile in the mature protein) replaces threonine with isoleucine at codon 742 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 performed for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 11462246, 17142622) and in an individual affected with myocardial infarction (PMID: 34615865). This variant has been identified in 2/251326 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.
Natera, Inc. RCV001186236 SCV002086867 uncertain significance Familial hypercholesterolemia 2021-03-31 no assertion criteria provided clinical testing

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