ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2050G>A (p.Ala684Thr)

gnomAD frequency: 0.00002  dbSNP: rs774730452
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237554 SCV000295842 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237554 SCV000503453 likely pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?)/software prediction damaging
Invitae RCV001057854 SCV001222369 likely pathogenic Familial hypercholesterolemia 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 684 of the LDLR protein (p.Ala684Thr). This variant is present in population databases (rs774730452, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11005141; Invitae). This variant is also known as A663T. ClinVar contains an entry for this variant (Variation ID: 252192). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV001057854 SCV001347392 uncertain significance Familial hypercholesterolemia 2023-03-22 criteria provided, single submitter clinical testing This missense variant (also known as p.Ala663Thr in the mature protein) replaces alanine with threonine at codon 684 of the LDLR protein. Computational prediction suggests that this variant may have a 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 two individuals affected with familial hypercholesterolemia (PMID: 11005141, 26608663). This variant has been identified in 4/251258 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.
All of Us Research Program, National Institutes of Health RCV000237554 SCV004818486 uncertain significance Hypercholesterolemia, familial, 1 2023-04-03 criteria provided, single submitter clinical testing This missense variant (also known as p.Ala663Thr in the mature protein) replaces alanine with threonine at codon 684 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 two Asian individuals affected with familial hypercholesterolemia (PMID: 11005141, 26608663). This variant has been identified in 4/251258 chromosomes (4/18394 East Asian 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237554 SCV000606586 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Natera, Inc. RCV001057854 SCV002086861 uncertain significance Familial hypercholesterolemia 2020-02-10 no assertion criteria provided clinical testing

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