Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Cardiovascular Biomarker Research Laboratory, |
RCV000211581 | SCV000266311 | uncertain significance | Familial hypercholesterolemia 1 | 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 |
LDLR- |
RCV000211581 | SCV000295318 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000211581 | SCV000503321 | uncertain significance | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting |
Molecular Genetics Laboratory, |
RCV000211581 | SCV000540894 | likely pathogenic | Familial hypercholesterolemia 1 | 2017-01-03 | criteria provided, single submitter | clinical testing | |
Gene |
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, |
RCV000211581 | SCV000839993 | likely pathogenic | Familial hypercholesterolemia 1 | 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. |
Color | RCV000775060 | SCV000909161 | likely pathogenic | Familial hypercholesterolemia | 2020-03-26 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000775060 | SCV000948046 | likely pathogenic | Familial hypercholesterolemia | 2019-12-19 | 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. |
CSER _CC_NCGL, |
RCV000148582 | SCV000190296 | uncertain significance | Hypercholesterolaemia | 2014-06-01 | no assertion criteria provided | research | |
Cardiovascular Genetics Laboratory, |
RCV000211581 | SCV000268607 | pathogenic | Familial hypercholesterolemia 1 | 2008-06-05 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000211581 | SCV000606368 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research |