ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.798T>A (p.Asp266Glu) (rs139043155)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148594 SCV000190309 uncertain significance Hypercholesterolaemia 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000172959 SCV000268586 pathogenic Familial hypercholesterolemia 2008-07-09 no assertion criteria provided clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000172959 SCV000599348 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
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 Familial hypercholesterolemia 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
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000172959 SCV000987028 likely pathogenic Familial hypercholesterolemia 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
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162020 SCV000189623 not provided not provided no assertion provided in vitro
GeneDx RCV000162020 SCV000234646 pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing The D266E pathogenic variant in the LDLR gene (also reported as D245E using alternative nomenclature) has been published previously in many individuals of various ethic backgrounds with diagnoses of FH (Hobbs et al., 1992; Kuhrova et al., 2001; Muller et al., 2004; Chmara et al., 2010; Amhad et al., 2012; Tichy et al., 2012; Stein et al., 2013; Kusters et al., 2013; Lange et al., 2014; Sharifi et al., 2016; Grenkowitz et al., 2016; Gabcova et al., 2017). Additionally, the D266E variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016). Although the D266E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies by Hobbs et al. (1992) demonstrate LDL receptor activity is 15-30% in patients with the D266E variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000172959 SCV000839980 likely pathogenic Familial hypercholesterolemia 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.
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000172959 SCV000212134 likely benign Familial hypercholesterolemia criteria provided, single submitter research
Invitae RCV000791360 SCV000544696 pathogenic Familial hypercholesterolemias 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 266 of the LDLR protein (p.Asp266Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant has been reported in many unrelated individuals affected with hypercholesterolemia (PMID: 1301956, 23375686, 21310417) and is established as a common cause of disease (PMID: 20663204, 22698793, 26238499).  This variant is also known as p.Asp245Glu in the literature. ClinVar contains an entry for this variant (Variation ID: 161287). A different missense substitution at this codon (p.Asp266Tyr) is reported to be deleterious (PMID: 11196104). This indicates that the asparagine residue is important for LDLR protein function. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000172959 SCV000294979 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000172959 SCV000606226 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844745 SCV000711397 pathogenic Familial hypercholesterolemia - homozygous 2017-07-10 criteria provided, single submitter clinical testing The p.Asp266Glu variant has been reported in over 100 individuals with familial hypercholesterolemia (FH; Bertolini 2013, Br?nne 2015, Brusgaard 2006, Chmara 20 10, Do 2015, Fouchier 2001, Hobbs 1992, Schmidt 2000, Sharifi 2016, Tichy 2012, Weiss 2000). Some publications refer to this variant as p.Asp245Glu. This varia nt has also been reported by other clinical laboratories in ClinVar (Variation I D: 161287) and has been identified in 10/126728 European chromosomes by the Geno me Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). This freque ncy is low enough to be consistent with the frequency of FH in the general popul ation. In vitro functional studies provide some evidence that the p.Asp266Glu va riant may impact protein function, resulting in 15-30% LDL receptor activity (Ho bbs 1992). Computational prediction tools and conservation analysis suggest that the p.Asp266Glu variant may impact the protein. Another likely pathogenic misse nse change at the same position (p.Asp266Tyr) has been reported in association t o FH (reported as p.Asp245Tyr, Weiss 2000). In summary, this variant meets crite ria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in a large number of affected individuals, low frequency in contro ls, presence of another likely pathogenic missense change at the same amino acid position, functional and computational evidence. ACMG/AMP Criteria applied: PS4 , PM2, PM5, PP3, PS3_supporting.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000172959 SCV000590848 likely pathogenic Familial hypercholesterolemia 2015-09-10 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000172959 SCV000540759 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
Robarts Research Institute,Western University RCV000172959 SCV000484680 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
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.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000172959 SCV000583741 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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