ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1529C>T (p.Thr510Met) (rs755154048)

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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 RCV000237591 SCV000295484 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237591 SCV000540811 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV001177034 SCV001341144 uncertain significance Familial hypercholesterolemia 2019-04-02 criteria provided, single submitter clinical testing
Invitae RCV001177034 SCV001379760 uncertain significance Familial hypercholesterolemia 2019-09-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 510 of the LDLR protein (p.Thr510Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs755154048, ExAC 0.02%). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 16542394, 22698793, 15199436). This variant is also known as T489M in the literature. ClinVar contains an entry for this variant (Variation ID: 251886). 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: "Deleterious"; PolyPhen-2: "Probably 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV000237591 SCV001440425 pathogenic Familial hypercholesterolemia 1 2019-01-01 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000237591 SCV001422918 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Thr510Met variant in LDLR has been reported in 8 individuals (5 Norwegian, 2 Danish, 1 Czech) with Familial Hypercholesterolemia, segregated with disease in 5 affected relatives from 1 family (PMID: 15199436, 22698793, 16542394), and has been identified in 0.005782% (2/34592) of Latino chromosomes and 0.0008793% (1/113732) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs755154048). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 251886). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP1_Moderate, PP3, PS4_Supporting (Richards 2015).

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