ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1816G>A (p.Ala606Thr) (rs72658865)

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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 RCV000238082 SCV000295674 uncertain significance Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000238082 SCV000540901 likely benign Familial hypercholesterolemia 1 2017-03-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000775078 SCV000909181 uncertain significance Familial hypercholesterolemia 2020-11-04 criteria provided, single submitter clinical testing This missense variant (also known as p.Ala585Thr in the mature protein) replaces alanine with threonine at codon 606 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a Spanish individual diagnosed with familial hypercholesterolemia (PMID: 19318025) and in one individual with clinical suspicion of familial hypercholesterolemia (PMID: 23340035). This variant has been identified in 9/251476 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 RCV000775078 SCV000949990 uncertain significance Familial hypercholesterolemia 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 606 of the LDLR protein (p.Ala606Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs72658865, ExAC 0.04%). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 23340035, 19318025). This variant is also known as p.Ala585Thr in the literature. ClinVar contains an entry for this variant (Variation ID: 252046). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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