ClinVar Miner

Submissions for variant NM_000527.4(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
Color RCV000775078 SCV000909181 uncertain significance Familial hypercholesterolemias 2018-07-22 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Ala585Thr in the mature protein) is located in the fifth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. While this variant has been reported in a Spanish individual diagnosed with hypercholesterolemia (PMID: 19318025), it has also been identified in 9/246254 chromosomes the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000775078 SCV000949990 pathogenic Familial hypercholesterolemias 2018-08-16 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 to segregate with familial hypercholesterolemia in two families, including family members who were homozygous for this variant (PMID: 11484166, 23158915), and observed in unrelated individuals affected with this disease (PMID: 20538126, 16092059, 9763532, 23340035, 19318025). This variant is also known as c.1879G>A (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"). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000238082 SCV000295674 uncertain significance Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000238082 SCV000540901 likely benign Familial hypercholesterolemia 2017-03-23 criteria provided, single submitter clinical testing

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