Submissions for variant NM_000527.5(LDLR):c.1238C>T (p.Thr413Met) (rs368562025)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomarker Research Laboratory,Mayo Clinic	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-LOVD, British Heart Foundation	RCV000211581	SCV000295318	likely pathogenic	Familial hypercholesterolemia 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	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,Centre for Cardiovascular Surgery and Transplantation	RCV000211581	SCV000540894	likely pathogenic	Familial hypercholesterolemia 1	2017-01-03	criteria provided, single submitter	clinical testing
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 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 Health, Inc	RCV000775060	SCV000909161	likely pathogenic	Familial hypercholesterolemia	2020-03-26	criteria provided, single submitter	clinical testing
Invitae	RCV000775060	SCV000948046	likely pathogenic	Familial hypercholesterolemia	2020-10-18	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 C1). 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. 5
CSER _CC_NCGL, University of Washington	RCV000148582	SCV000190296	uncertain significance	Hypercholesterolaemia	2014-06-01	no assertion criteria provided	research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211581	SCV000268607	pathogenic	Familial hypercholesterolemia 1	2008-06-05	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211581	SCV000606368	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research