ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1238C>T (p.Thr413Met) (rs368562025)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148582 SCV000190296 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Cardiovascular Biomarker Research Laboratory,Mayo Clinic RCV000211581 SCV000266311 uncertain significance Familial hypercholesterolemia 2015-08-31 criteria provided, single submitter research MAF =<0.3%, likely pathogenic based on the integrative in-silico score, previously reported as P/LP in the literature
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211581 SCV000268607 pathogenic Familial hypercholesterolemia 2008-06-05 no assertion criteria provided clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211581 SCV000503321 uncertain significance Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Color RCV000775060 SCV000909161 uncertain significance Familial hypercholesterolemias 2018-10-20 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Thr392Met in the mature protein) is located in the LDLR type B repeat 1 of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 11668627, 11857755, 15015036, 17539906, 19843101, 25682026), as well as in an individual affected with myocardial infarction (PMID: 25487149). This variant has also been identified in 9/246070 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000519267 SCV000617508 likely pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing The T413M variant in the LDLR gene has been reported previously in at least 5 unrelated individuals from various ethnic backgrounds with familial hypercholesterolemia (Wang et al., 2001; Bunn et al., 2002; Mihaylov et al., 2004; Wang et al., 2005). Additionally, the T413M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T413M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although this substitution occurs at a position that is not conserved, methionine is not tolerated at this position in any species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E408K, E408V, K411E, L414R, R416W, R416P, R416Q) have been reported in the Human Gene Mutation Database in association with familial hypercholesterolemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret T413M as a likely pathogenic variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000211581 SCV000839993 likely pathogenic Familial hypercholesterolemia 2017-10-23 criteria provided, single submitter clinical testing This c.1238C>T (p.Thr413Met) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 11857755, 17539906, 19843101, 11668627, 15015036, 25682026) or myocardial infarction (PMID: 25487149). The p.Thr413Met variant occurs within the low-density lipoprotein receptor repeat class B domain of the LDLR protein (https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi?seqinput=NP_001182729.1 ). The c.1238C>T variant is rare in the general population and threonine at position 413 of the LDLR protein is highly evolutionarily conserved. The c.1238C>T (p.Thr413Met) variant in the LDLR gene is classified as likely pathogenic.
Invitae RCV000775060 SCV000948046 likely pathogenic Familial hypercholesterolemias 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 413 of the LDLR protein (p.Thr413Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs368562025, ExAC 0.003%). This variant has been observed in individual(s) with familial hypercholesterolemia (FH) (PMID: 11857755, 25682026, 20236128, 25487149, 19843101, 22883975, 17539906, 15199436, Invitae). In at least one individual affected with homozygous FH the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.T392M in the literature. ClinVar contains an entry for this variant (Variation ID: 161276). 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 C15"). 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.
LDLR-LOVD, British Heart Foundation RCV000211581 SCV000295318 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211581 SCV000606368 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211581 SCV000540894 likely pathogenic Familial hypercholesterolemia 2017-01-03 criteria provided, single submitter clinical testing

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