rs139043155

Positions:

• chr19-11106668-T-A
• chr19-11106668-T-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PP4 PS3_Moderate PS4 PM5_Strong PP1_Strong

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023765/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:37 U:2 B:1 O:1
• Conservation: PhyloP100: -1.19

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.798T>A	p.Asp266Glu	missense_variant	5/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.798T>A	p.Asp266Glu	missense_variant	5/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251482 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000793 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:37 Uncertain:2 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:21 Benign:1

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely benign, criteria provided, single submitter	research	Institute for Integrative and Experimental Genomics, University of Luebeck	-	- -
Likely pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jul 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 24, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 06, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Sep 10, 2015	- -
Likely pathogenic, 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	Dec 16, 2016	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 -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 06, 2022	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 07, 2021	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jul 09, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 07, 2024	Criteria applied: PS4,PM5_STR,PP1_STR,PS3_MOD,PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Oct 30, 2017	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 -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jun 04, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Mar 13, 2019	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. -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -

not provided Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 27, 2021	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. -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 19, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 27, 2022	PP1_strong, PP4, PM2, PM5_strong, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	LDLR: PP1:Strong, PM5, PS4:Moderate, PM2:Supporting, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Familial hypercholesterolemia Pathogenic:5 Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2020	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 05, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 08, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 24, 2020	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. -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 15, 2020

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. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Apr 25, 2022

ACMG categories: PS1,PS4,PM2,PP5,BP1 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2023

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. -

Hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.;.;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.97	D;.;.;.;.
Vest4		0.85
MutPred		0.94		Gain of ubiquitination at K262 (P = 0.1283);Gain of ubiquitination at K262 (P = 0.1283);.;.;Gain of ubiquitination at K262 (P = 0.1283);
MVP		1.0
MPC		0.76
ClinPred		0.96	D
GERP RS		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139043155; hg19: chr19-11217344;