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

gnomAD frequency: 0.00001  dbSNP: rs368562025

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211581	SCV001960926	likely pathogenic	Hypercholesterolemia, familial, 1	2021-06-09	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1238C>T (p.Thr413Met) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Moderate, PP1 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006533 (0.007%) in South Asian (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 6 index cases. PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from GeneDx laboratory. PP4 - Variant meets PM2. Variant identified in 6 index cases (2 cases from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with DLCN criteria, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria).
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000211581	SCV000266311	uncertain significance	Hypercholesterolemia, familial, 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	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	RCV000211581	SCV000503321	uncertain significance	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2017-01-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000519267	SCV000617508	likely pathogenic	not provided	2024-02-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24055113, 25487149, 11668627, 11857755, 25637381, 15015036, 15576851, 15199436, 17539906, 28145427, 32015373, 32719484, 32522009, 30586733, 31447099, 34037665, 25682026, 27783906, 22883975, 35913489, 33854068, 34906840, Gratton2023[CaseReport], 37409534, 37443404, 35460704)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000211581	SCV000839993	likely pathogenic	Hypercholesterolemia, familial, 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 Diagnostics, LLC DBA Color Health	RCV000775060	SCV000909161	likely pathogenic	Familial hypercholesterolemia	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Thr392Met in the mature protein) replaces threonine with methionine at codon 413 in the LDLR type B repeat 1 of the EGF precursor homology domain of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have indicated no significant change in LDLR protein expression and function due to this variant (PMID: 32015373, 34029164). This variant has been reported in over twenty heterozygous individuals affected with familial hypercholesterolemia (PMID: 11668627, 11857755, 15015036, 15199436, 15576851, 17539906, 19843101, 22883975, 25682026, 31993549, 34037665; ClinVar SCV001960926.1). It has also been reported in an individual affected with myocardial infarction (PMID: 25487149) and in an individual affected with low circulating HDL-C (PMID: 35460704). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 34029164). This variant has been reported to segregate with disease in two members of a family (ClinVar SCV001960926.1). This variant has been identified in 7/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775060	SCV000948046	pathogenic	Familial hypercholesterolemia	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 413 of the LDLR protein (p.Thr413Met). This variant is present in population databases (rs368562025, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 11857755, 20236128, 25682026; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 161276). 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%. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000519267	SCV002502862	likely pathogenic	not provided	2022-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362782	SCV002662751	likely pathogenic	Cardiovascular phenotype	2023-02-01	criteria provided, single submitter	clinical testing	The p.T413M variant (also known as c.1238C>T), located in coding exon 9 of the LDLR gene, results from a C to T substitution at nucleotide position 1238. The threonine at codon 413 is replaced by methionine, an amino acid with similar properties. This variant (also described as p.T392M) has been detected in individuals with familial hypercholesterolemia (FH); however, clinical details were limited in most cases (Bunn CF et al. Hum. Mutat., 2002 Mar;19:311; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Taylor A et al. Clin. Genet., 2007 Jun;71:561-8; Safarova MS et al. Eur. J. Hum. Genet., 2017 04;25:410-415). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Do R et al. Nature, 2015 Feb;518:102-6). This alteration was also detected in one control subject from a myocardial infarction study (Khera AV et al. Circulation, 2019 03;139:1593-1602). This alteration has also been reported in additional subjects with FH and as a compound heterozygote in a child with features of FH (personal communication). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000211581	SCV002813855	likely pathogenic	Hypercholesterolemia, familial, 1	2021-12-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000775060	SCV002819468	likely pathogenic	Familial hypercholesterolemia	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1238C>T (p.Thr413Met) results in a non-conservative amino acid change located in the EGF spacer domain (Dong_2022) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 253468 control chromosomes (gnomAD and publication data). c.1238C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia, Myocardial infarction or Coronary artery disease (Bunn_2022, Leren_2004, Taylor_2007, Hooper_2012, Do_2014, Khera_2016, Wald_2016, Saadatagah_2021, Sturm_2021). These data indicate that the variant is likely to be associated with disease. At least one functional study showed LDLR activity (LDL binding and uptake) of this variant determined by flow cytometry and indicated LDL uptake as 85% WT and LDL binding as 80% WT, but no effect on protein expression level in transfected cellls (Galicia-Garcia_2020). Twelve ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=3), likely pathogenic (n=8) and pathogenic (n=1), including one expert panel (ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel) classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000211581	SCV004027629	likely pathogenic	Hypercholesterolemia, familial, 1	2023-05-08	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM2_SUP,PP1,PP3,PP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000519267	SCV004562712	likely pathogenic	not provided	2023-10-17	criteria provided, single submitter	clinical testing	The LDLR c.1238C>T; p.Thr413Met variant (rs368562025) is reported in the literature in multiple individuals affected with familial hypercholesterolemia and myocardial infarction (Do 2015, Dong 2022, eMERGE Consortium 2019, Sturm 2021, Sustar 2022). This variant is also reported as likely pathogenic by an expert panel in ClinVar (Variation ID: 161276). This variant is found in the general population with an overall allele frequency of 0.003% (7/251176 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.692). Based on available information, this variant is considered to be likely pathogenic. References: Do R, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015 Feb 5;518(7537):102-6. PMID: 25487149. Dong W et al. Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia. J Lipid Res. 2022 Jun;63(6):100209. PMID: 35460704. eMERGE Consortium et al. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. Am J Hum Genet. 2019 Sep 5;105(3):588-605. PMID: 31447099. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665. Sustar U et al. Universal screening for familial hypercholesterolemia in 2 populations. Genet Med. 2022 Oct;24(10):2103-2111. PMID: 35913489.
All of Us Research Program, National Institutes of Health	RCV000211581	SCV004820282	likely pathogenic	Hypercholesterolemia, familial, 1	2023-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 413 in the LDLR type B repeat 1 of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Thr392Met in the mature protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have indicated no significant change in LDLR protein expression and function due to this variant (PMID: 32015373, 34029164). This variant has been reported in over twenty heterozygous individuals affected with familial hypercholesterolemia (PMID: 11668627, 11857755, 15015036, 15199436, 15576851, 17539906, 19843101, 22883975, 25682026, 31993549; ClinVar SCV001960926.1) and in an individual affected with myocardial infarction (PMID: 25487149). This variant has been observed in an individual with severe familial hypercholesterolemia who also carried a pathogenic truncation variant in the same gene (PMID: 34029164). This variant has been reported to segregate with disease in two members of a family (ClinVar SCV001960926.1). This variant has been identified in 7/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
CSER _CC_NCGL, University of Washington	RCV002051669	SCV000190296	uncertain significance	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211581	SCV000268607	pathogenic	Hypercholesterolemia, familial, 1	2008-06-05	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211581	SCV000606368	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000775060	SCV002086415	likely pathogenic	Familial hypercholesterolemia	2020-08-13	no assertion criteria provided	clinical testing