Submissions for variant NM_000527.5(LDLR):c.798T>A (p.Asp266Glu)

gnomAD frequency: 0.00004  dbSNP: rs139043155

Total submissions: 41

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000172959	SCV001960912	pathogenic	Hypercholesterolemia, familial, 1	2021-06-07	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM5_Strong, PM2, PS3_Moderate 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: PS4 - Variant meets PM2. Identified in over 10 unrelated index cases from Center of molecular biology and gene therapy with FH diagnosis. PP1_strong - variant segregates with phenotype in over 30 informative meiosis in several families from different laboratories. PM5_strong - Four more missense variants described in same codon: --- 3 variants classified as Pathogenic, so PM5_Strong is met. PM2 - PopMax MAF = 0.00007740 (0.008%) in european non-finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay: PMID 1301956: Hmz patients' fibroblasts, 125I-LDL assays - results - 15-30% LDLR activity (but all cycle was tested) ---- Overall LDLR activity is below 70% of wild-type activity, so PS3_moderate is Met. PP4 - Variant meets PM2. Identified in over 10 unrelated index cases from Center of molecular biology and gene therapy with FH diagnosis.
CSER _CC_NCGL, University of Washington	RCV002051680	SCV000190309	uncertain significance	Hypercholesterolemia	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Institute for Integrative and Experimental Genomics, University of Luebeck	RCV000172959	SCV000212134	likely benign	Hypercholesterolemia, familial, 1		criteria provided, single submitter	research
GeneDx	RCV000162020	SCV000234646	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	Published functional studies classify D266E as partially transport-defective with LDL receptor activity at 15-30% compared to controls (PMID: 1301956); Also known as FH Cincinnati-1 and p.D245E; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24014831, 25637381, 20145306, 23375686, 25487149, 25647241, 1301956, 26892515, 22881376, 15556092, 23064986, 11052664, 11524740, 28008010, 24507775, 27596133, 29083407, 30795984, 31401775, 34426522, 32719484, 33740630, 32041611, 33269076, 34037665, 31447099, 32770674, 33418990, 23833242, 35741760, 33955087, 26036859, 35913489, 35626767, 22698793, 27824480)
LDLR-LOVD, British Heart Foundation	RCV000172959	SCV000294979	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000172959	SCV000484680	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	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	RCV000172959	SCV000503238	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , family members = 11 with co-segregation / FH-Cincinnati-1, 15 to 30% LDLR activity / Software predictions: Damaging
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000172959	SCV000540759	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791360	SCV000544696	pathogenic	Familial hypercholesterolemia	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 266 of the LDLR protein (p.Asp266Glu). This variant is present in population databases (rs139043155, gnomAD 0.008%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 20663204, 21310417, 22698793, 23375686, 26238499). This variant is also known as p.Asp245Glu. ClinVar contains an entry for this variant (Variation ID: 161287). 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%. This variant disrupts the p.Asp266 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11196104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000172959	SCV000583741	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000172959	SCV000590848	likely pathogenic	Hypercholesterolemia, familial, 1	2015-09-10	criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000172959	SCV000599348	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844745	SCV000711397	pathogenic	Homozygous familial hypercholesterolemia	2020-11-15	criteria provided, single submitter	clinical testing	The p.Asp266Glu variant (also described as p.Asp245Glu in the literature) has been reported in over 100 individuals with familial hypercholesterolemia (FH; Bertolini 2013 PMID: 23375686, Brænne 2015 PMID: 26036859, Brusgaard 2006 PMID: 16542394, Chmara 2010 PMID: 20145306, Do 2015 PMID: 25487149, Fouchier 2001 PMID: 11810272, Hobbs 1992 PMID: 1301956, Schmidt 2000 PMID: 10657581, Sharifi 2016 PMID: 26892515, Tichý 2012 PMID: 22698793, Weiss 2000 PMID: 11196104) and reportedly segregated with disease in numerous affected relatives from multiple families (Clinvar, Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation SCV000540759.1). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 161287) and has been identified in 0.008% (10/129194) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies provide some evidence that the p.Asp266Glu variant may impact protein function, resulting in 15-30% LDL receptor activity (Hobbs 1992 PMID: 1301956). Computational prediction tools and conservation analysis suggest that the p.Asp266Glu variant may impact the protein. Another likely pathogenic missense change at the same position (p.Asp266Tyr) has been reported in association to FH (reported as p.Asp245Tyr, Weiss 2000 PMID: 11196104). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PM5_Supporting, PM2_Supporting , PP3, PS3_supporting.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000172959	SCV000839980	likely pathogenic	Hypercholesterolemia, familial, 1	2017-07-06	criteria provided, single submitter	clinical testing	This c.798T>A (p.Asp266Glu) variant has previously been detected in multiple patients with familial hypercholesterolemia [PMID 1301956, 11196104, 25637381, 25487149, 11810272, 16542394, 21310417, also reported as FH Cincinnati-1 (legacy: 245)]. Additional patients with hypercholesterolemia have been reported with variants located at the same amino acid position (p.Asp266Asn, p.Asp266Gly, p.Asp266Tyr and p.Asp266Val). This variant was observed in ten heterozygous individuals in the gnomAD database (http://gnomad.broadinstitute.org/variant/19-11217344-T-A This variant is highly conserved in mammals and computer-based algorithms predict this p.Asp266Glu change to be deleterious. It is thus classified as likely pathogenic.
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000172959	SCV000987028	likely pathogenic	Hypercholesterolemia, familial, 1	2017-10-30	criteria provided, single submitter	clinical testing	The nucleotide substitution c.798T>A causes an exchange of the amino acid aspartate acid to glutamate at position 266 (p.Asp266Glu, D266E). This mutation has already been described in patients with hypercholesterolemia and is therefore classified as pathogenic. PMID: 1301956, 11810272, 16542394
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000172959	SCV000996264	likely pathogenic	Hypercholesterolemia, familial, 1	2019-03-13	criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with familial hypercholesterolemia or early-onset myocardial infarction (PMID: 23375686, 25487149). Functional studies by Hobbs et al. (PMID 1301956) demonstrated that LDL receptor activity in patients with the p.Asp266Glu variant is 15-30% of wild type allele. This change is reported in ClinVar by other clinical laboratories (Variation ID 161287), as well as described as disease causing variant in the Human Disease Mutation Database. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/277250) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.798T>A (p.Asp266Glu) variant on protein function. Based on the available evidence, the c.798T>A (p.Asp266Glu) variant is classified as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000162020	SCV001246006	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	LDLR: PP1:Strong, PM5, PS4:Moderate, PM2:Supporting, PS3:Supporting
Institute of Human Genetics, University of Leipzig Medical Center	RCV000172959	SCV001251400	pathogenic	Hypercholesterolemia, familial, 1	2024-08-07	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM5_STR,PP1_STR,PS3_MOD,PM2
Color Diagnostics, LLC DBA Color Health	RCV000791360	SCV001355074	pathogenic	Familial hypercholesterolemia	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp245Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 266 in the sixth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using cells from a homozygous carrier has shown that this variant causes a significant decrease of LDLR (PMID: 1301956). This variant has been reported in numerous individuals affected with familial hypercholesterolemia and is known to be a common cause of disease in the Czech, German and Austrian populations (PMID: 1301956, 20663204, 21310417, 22698793, 23375686, 26238499, 27596133, 31345425, 33269076, 33418990, 33740630, 34037665, 35741760). This variant has been identified in 10/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon (p.Asp266Asn, p.Asp266Gly, and p.Asp266Val) are considered to be disease-causing (ClinVar variation ID: 226334, 251457, and 251458), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000172959	SCV001432578	likely pathogenic	Hypercholesterolemia, familial, 1	2019-06-04	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000791360	SCV001442758	pathogenic	Familial hypercholesterolemia	2020-10-08	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.798T>A (p.Asp266Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251482 control chromosomes. c.798T>A has been widely reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Tichy_2012, Goldmann_2010, Duskova_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Hobbs_1992). The most pronounced variant effect results in 15%-30% of normal LDL receptor activity. Seventeen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic/pathogenic, n=16). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	RCV000791360	SCV001482460	uncertain significance	Familial hypercholesterolemia		criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000162020	SCV001715242	pathogenic	not provided	2022-10-27	criteria provided, single submitter	clinical testing	PP1_strong, PP4, PM2, PM5_strong, PS3, PS4_moderate
Revvity Omics, Revvity	RCV000172959	SCV002017134	pathogenic	Hypercholesterolemia, familial, 1	2022-09-24	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000172959	SCV002059223	pathogenic	Hypercholesterolemia, familial, 1	2019-07-05	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000162020	SCV002501923	pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV004584356	SCV002506420	pathogenic	See cases	2022-04-25	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PS4,PM2,PP5,BP1
Ambry Genetics	RCV002408658	SCV002675705	pathogenic	Cardiovascular phenotype	2023-10-06	criteria provided, single submitter	clinical testing	The c.798T>A (p.D266E) alteration is located in coding exon 5 of the LDLR gene. This alteration results from a T to A substitution at nucleotide position 798, causing the aspartic acid (D) at amino acid position 266 to be replaced by a glutamic acid (E). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (10/282892) total alleles studied. The highest observed frequency was 0.008% (10/129194) of European (non-Finnish) alleles. This alteration, referred to as D245E, was described in multiple individuals from familial hypercholesterolemia (FH) cohorts, and reduced LDL-R activity was reported in patients' cultured fibroblasts (Hobbs, 1992; Schmidt, 2000; Fouchier, 2001; Brusgaard, 2006). Multiple other alterations at the same codon, c.796G>A (p.D266N), c.796G>C (p.D266H), c.797A>G (p.D266G), c.797A>T (p.D266V), and c.796G>T (p.266Y), have been described in association with FH (Weiss, 2000; Fouchier, 2001; Yu, 2002; Chmara, 2010; Xiang, 2017). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000162020	SCV002774352	pathogenic	not provided	2021-08-27	criteria provided, single submitter	clinical testing	The LDLR c.798T>A (p.Asp266Glu) variant has been reported in the published literature in individuals affected with familial hypercholesterolemia (FH) (PMIDs: 33269076 (2021), 26892515 (2016), 23375686 (2013), 22698793 (2012), 20145306 (2010), 16542394 (2006), 15199436 (2004), 10657581 (2000)). In addition, this variant is reported to result in reduced LDLR receptor activity (PMID: 1301956 (1992)). The frequency of this variant in the general population, 0.000077 (10/129194 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000172959	SCV002785862	pathogenic	Hypercholesterolemia, familial, 1	2022-04-06	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000172959	SCV004046793	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	not provided
All of Us Research Program, National Institutes of Health	RCV000172959	SCV004820215	pathogenic	Hypercholesterolemia, familial, 1	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp245Glu in the mature protein) replaces aspartic acid with glutamic acid at codon 266 in the sixth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using cells from a homozygous carrier has shown that this variant causes a significant decrease of LDLR (PMID: 1301956). This variant has been reported in numerous individuals affected with familial hypercholesterolemia and is known to be a common cause of disease in the Czech, German and Austrian populations (PMID: 1301956, 20663204, 21310417, 22698793, 23375686, 26238499, 27596133, 31345425, 33269076, 33418990, 33740630, 34037665, 35741760). This variant has been identified in 10/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon (p.Asp266Asn, p.Asp266Gly, and p.Asp266Val) are considered to be disease-causing (ClinVar variation ID: 226334, 251457, and 251458), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000791360	SCV005045763	pathogenic	Familial hypercholesterolemia	2020-09-24	criteria provided, single submitter	clinical testing	The c.798T>A (p.Asp266Glu) in the LDLR gene is located on the exon 5 and is predicted to replace the aspartic acid with glutamic acid at codon 266 (p.Asp266Glu). This variant has been reported in more than 10 unrelated individuals affected with familial hypercholesterolemia (PMID: 15359125, 32793292, 22883975). Co-segregation of this variant with phenotype over 30 meioses in multiple families has been reported by different laboratories according to the ClinGen expert panel. LDL assay using homozygote patient fibroblast showed 15-30% of normal LDLR activity and a negative functional impact (PMID: 1301956). This variant has been reported in ClinVar (ID: 161287) and reviewed as a pathogenic variant by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel. At the same codon position Asp266, four alternative variants (p.Asp266Asn, p.Asp266Tyr, p.Asp266Val, p.Asp266Gly) have also been classified as pathogenic or likely pathogenic in ClinVar (ClinVar IDs: 226334, 251456, 251458, 251457). This variant is rare in the general population according to gnomAD (10/282892). Therefore, the c.798T>A (p.Asp266Glu) variant in the LDLR gene has been classified as pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162020	SCV000189623	not provided	not provided		no assertion provided	in vitro
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000172959	SCV000268586	pathogenic	Hypercholesterolemia, familial, 1	2008-07-09	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000172959	SCV000606226	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000162020	SCV000925128	pathogenic	not provided	2016-10-19	no assertion criteria provided	provider interpretation	The patient had genetic testing for the familial hypercholesterolemia panel with Ambry Genetics. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified (see report below): p.Asp266Glu (c.798T>A) in the LDLR gene (NM_000527.4) The lab classifies this variant as likely pathogenic. Given sufficient case data we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in more than 20 unrelated cases of familial hypercholesterolemia (not including this patient's family). This variant is also reported in the literature as p.Asp245Glu (c.798T>A). Hobbs, et al. 1992 first reported this variant in his cohort of patients with FH. The patient was diagnosed with hyperlipidemia type 2B (FH), and had 15-30 % of residual LDLR activity. Schmidt, et al. 2000 reported this variant in 16 unrelated index cases in Australia. They were all clinically diagnosed with familial hypercholesterolemia and is one of the most common variants identified in his Australian cohort of 950 index cases. Fouchier SW et al. 2001 identified this variant and a similar variant at the same position, D245N, in his cohort. Brusgaard, et al. 2006 also reported this variant in three individuals who had a clinical diagnosis of familial hypercholesterolemia. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.998). The aspartic acid at codon 266 is conserved across species, as are some neighboring amino acids. Other variants have been reported in association with disease at this codon (D245N). There are two individuals with variation at codon 266 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 10, 2016). The average coverage at that site in ExAC is 40x.
Clinical Genetics, Academic Medical Center	RCV000162020	SCV001923193	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000162020	SCV001963098	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000791360	SCV002086388	pathogenic	Familial hypercholesterolemia	2020-08-05	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000172959	SCV004099452	pathogenic	Hypercholesterolemia, familial, 1	2023-10-30	no assertion criteria provided	clinical testing