VCV000161287.85 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

41 submissions

40 submitters

7 conditions

Reviewed by expert panel

Pathogenic

Jun 2021 by ClinGen Famili… FDA Recognized Database

for Hypercholesterolemia, familial, 1

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 161287 Accession: VCV000161287.85

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11106668 (GRCh38) [ NCBI UCSC ] 19: 11217344 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 7, 2014	Oct 20, 2024	Jun 7, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.798T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Asp266Glu	missense
NM_000527.2:c.798T>A
NM_001195798.2:c.798T>A	NP_001182727.1:p.Asp266Glu	missense
NM_001195799.2:c.675T>A	NP_001182728.1:p.Asp225Glu	missense
NM_001195800.2:c.314-724T>A		intron variant
NM_001195803.2:c.417T>A	NP_001182732.1:p.Asp139Glu	missense
NC_000019.10:g.11106668T>A
NC_000019.9:g.11217344T>A
NG_009060.1:g.22288T>A
LRG_274:g.22288T>A
LRG_274t1:c.798T>A	LRG_274p1:p.Asp266Glu
	P01130:p.Asp266Glu

... more HGVS ... less HGVS

Protein change

D266E, D225E, D139E

Other names

NP_000518.1:p.D266E
NM_000527.5(LDLR):c.798T>A

Canonical SPDI

NC_000019.10:11106667:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

unknown functional consequence

unclear [submitted by Dept. of Genetics and Pharmacogenomics, Merck Research Labs]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

UniProtKB: P01130#VAR_005347 dbSNP: rs139043155 ClinGen: CA023765 LDLR-LOVD, British Heart Foundation: LDLR_000117 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LDLR		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4076	4352

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV000162020.51
Hypercholesterolemia, familial, 1	Pathogenic (22)	reviewed by expert panel	Jun 7, 2021	RCV000172959.53
Homozygous familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Nov 15, 2020	RCV000844745.15
Familial hypercholesterolemia	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Jan 29, 2024	RCV000791360.25
Hypercholesterolemia	Uncertain significance (1)	criteria provided, conflicting classifications	Jun 1, 2014	RCV002051680.13
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Oct 6, 2023	RCV002408658.9
See cases	Pathogenic (1)	criteria provided, single submitter	Apr 25, 2022	RCV004584356.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 07, 2021)	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1) Method: curation	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel FDA Recognized Database Accession: SCV001960912.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/da36a90c-1718-424e-83fa-5e42e5af70fa Comment: 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 … (more) 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. (less)
Likely pathogenic (Mar 25, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: literature only	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	LDLR-LOVD, British Heart Foundation Accession: SCV000294979.2 First in ClinVar: Jul 29, 2016 Last updated: Oct 13, 2018	Publications: PubMed (8) PubMed: 10657581‚ 11196104‚ 11810272‚ 1301956‚ 15199436‚ 16542394‚ 20145306‚ 21310417 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1 Observation 3: Number of individuals with the variant: 1 Observation 4: Number of individuals with the variant: 1 Observation 5: Number of individuals with the variant: 1 Observation 6: Number of individuals with the variant: 1 Observation 7: Number of individuals with the variant: 1 Observation 8: Number of individuals with the variant: 1
Likely pathogenic (Jul 06, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000839980.1 First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018	Comment: 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 … (more) 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. (less)
Pathogenic (Nov 15, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Homozygous familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711397.4 First in ClinVar: Apr 09, 2018 Last updated: May 29, 2021	Publications: PubMed (14) PubMed: 23375686‚ 21310417‚ 25637381‚ 1301956‚ 26036859‚ 20145306‚ 25487149‚ 26892515‚ 10657581‚ 16542394‚ 20663204‚ 11810272‚ 11196104‚ 22698793 Comment: 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, … (more) 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, BrÃ¦nne 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, TichÃ½ 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. (less) Number of individuals with the variant: 22
Pathogenic (Jul 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059223.1 First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022
Pathogenic (Apr 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002785862.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Aug 27, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002774352.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 06, 2024	Publications: PubMed (29) PubMed: 26892515‚ 26036859‚ 25647241‚ 15199436‚ 1301956‚ 11754108‚ 11196104‚ 10657581‚ 23375686‚ 21310417‚ 22698793‚ 20145306‚ 16542394‚ 11810272‚ 20663204‚ 33269076‚ 24507775‚ 25487149‚ 25637381‚ 29083407‚ 30795984‚ 31447099‚ 32041611‚ 32719484‚ 32770674‚ 33418990‚ 33740630‚ 34037665‚ 34426522 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715242.3 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Other databases https://www.ncbi.nlm.nih.gov/cli… https://www.ncbi.nlm.nih.gov/clinvar/variation/161287/?new_evidence=false Comment: PP1_strong, PP4, PM2, PM5_strong, PS3, PS4_moderate Number of individuals with the variant: 5
Pathogenic (May 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001355074.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (13) PubMed: 1301956‚ 20663204‚ 21310417‚ 22698793‚ 23375686‚ 26238499‚ 27596133‚ 31345425‚ 33269076‚ 33418990‚ 33740630‚ 34037665‚ 35741760 Comment: 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 … (more) 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. (less)
Pathogenic (Sep 24, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	familial hypercholesterolemia Affected status: unknown Allele origin: unknown	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV005045763.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (Jun 07, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000234646.9 First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024	Comment: 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 … (more) 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) (less)
Pathogenic (Oct 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246006.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: LDLR: PP1:Strong, PM5, PS4:Moderate, PM2:Supporting, PS3:Supporting Number of individuals with the variant: 7
Likely benign (-)	criteria provided, single submitter (Submitter's publication) Method: research	Familial Hypercholesterolemia (Autosomal dominant inheritance) Affected status: no Allele origin: germline	Institute for Integrative and Experimental Genomics, University of Luebeck Accession: SCV000212134.1 First in ClinVar: Jun 20, 2015 Last updated: Jun 20, 2015	Publications: PubMed (1) PubMed: 26036859
Uncertain significance (Jun 01, 2014)	criteria provided, single submitter (Amendola et al. (Genome Res. 2015)) Method: research	Hypercholesterolaemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190309.2 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript	Publications: PubMed (1) PubMed: 25637381 Comment: Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Likely pathogenic (-)	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016)) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Robarts Research Institute, Western University Accession: SCV000484680.1 First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016	Number of individuals with the variant: 1
Likely pathogenic (Dec 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix Accession: SCV000503238.1 First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016	Comment: subjects mutated among 2600 FH index cases screened = 4 , family members = 11 with co-segregation / FH-Cincinnati-1, 15 to 30% LDLR activity / … (more) 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 (less) Number of individuals with the variant: 4
Likely pathogenic (Nov 05, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation Additional submitter: Centre of Molecular Biology and Gene Therapy, University Hospital Brno Accession: SCV000540759.1 First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017	Publications: PubMed (2) PubMed: 22698793‚ 11754108 Number of individuals with the variant: 247 Clinical Features: Hypercholesterolemia (present) , Ischemic stroke (present) , Xanthelasma (present) , Tendon xanthoma (present) , Corneal arcus (present) Family history: yes Age: 3-71 years Sex: mixed Ethnicity/Population group: Caucasian Geographic origin: Czech Republic Tissue: Whole blood
Pathogenic (Mar 30, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Hypercholesterolemia Affected status: yes Allele origin: germline	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille Accession: SCV000583741.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 Comment: ACMG Guidelines: Pathogenic (ii)	Number of individuals with the variant: 3 Clinical Features: Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present) Indication for testing: Familial Hypercholesterolemia Sex: mixed Geographic origin: France Comment on evidence: Dutch Lipid Clinic Scoring : Probable FH Secondary finding: no
Likely pathogenic (Sep 10, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000590848.1 First in ClinVar: Aug 19, 2017 Last updated: Aug 19, 2017	Publications: PubMed (2) PubMed: 1301956‚ 1734910 Clinical Features: hypercholesterolemia (present) , obesity (present) Age: 10-19 years Sex: female
Likely pathogenic (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation, literature only	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: not applicable, unknown Allele origin: germline, not applicable	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000599348.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (1) PubMed: 1301956 Observation 1: Comment on evidence: %MAF(ExAC):0.001648 Observation 2: Comment on evidence: Assay Description:Hmz patients' fibroblasts, 125I-LDL assays Result: 15-30% LDLR activity
Likely pathogenic (Oct 30, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen Accession: SCV000987028.1 First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019	Comment: 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 … (more) 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 (less)
Likely pathogenic (Mar 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HYPERCHOLESTEROLEMIA, FAMILIAL Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996264.1 First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Likely pathogenic (Jun 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia Accession: SCV001432578.1 First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020	Observation 1: Number of individuals with the variant: 1 Clinical Features: Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present) Observation 2: Number of individuals with the variant: 1 Clinical Features: Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present) Observation 3: Number of individuals with the variant: 1 Clinical Features: Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Pathogenic (Oct 08, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001442758.1 First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020	Publications: PubMed (6) PubMed: 1301956‚ 21310417‚ 23375686‚ 22698793‚ 20663204‚ 30795984 Comment: 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 … (more) 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. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine Accession: SCV001482460.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Publications: PubMed (1) PubMed: 29261184 Age: 60-69 years Sex: female
Pathogenic (Jan 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501923.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (15) PubMed: 1301956‚ 25637381‚ 23375686‚ 25487149‚ 32041611‚ 32719484‚ 24507775‚ 33740630‚ 29083407‚ 30795984‚ 33418990‚ 33269076‚ 32770674‚ 34037665‚ 31447099 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital of Duesseldorf Accession: SCV004046793.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023
Pathogenic (Sep 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017134.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000544696.10 First in ClinVar: Apr 16, 2017 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 28492532‚ 1301956‚ 20663204‚ 21310417‚ 22698793‚ 23375686‚ 26238499‚ 11196104 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004820215.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (13) PubMed: 1301956‚ 20663204‚ 21310417‚ 22698793‚ 23375686‚ 26238499‚ 27596133‚ 31345425‚ 33269076‚ 33418990‚ 33740630‚ 34037665‚ 35741760 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 15
Pathogenic (Oct 06, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002675705.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (12) PubMed: 1301956‚ 2088165‚ 10657581‚ 11196104‚ 11810272‚ 12417285‚ 16542394‚ 20145306‚ 23375686‚ 25487149‚ 27824480‚ 28235710 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002506420.2 First in ClinVar: May 07, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: PS1,PS4,PM2,PP5,BP1 Number of individuals with the variant: 1 Clinical Features: Hypercholesterolemia (present) Age: 50-59 years Sex: female Tissue: blood
Pathogenic (Aug 07, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001251400.10 First in ClinVar: May 31, 2020 Last updated: Oct 13, 2024	Comment: Criteria applied: PS4,PM5_STR,PP1_STR,PS3_MOD,PM2 Clinical Features: Increased LDL cholesterol concentration (present) Sex: female
Pathogenic (Jul 09, 2008)	no assertion criteria provided Method: clinical testing	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital Accession: SCV000268586.1 First in ClinVar: May 21, 2016 Last updated: May 21, 2016	Number of individuals with the variant: 2
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001923193.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000606226.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017
Pathogenic (Oct 19, 2016)	no assertion criteria provided Method: provider interpretation	not provided Affected status: unknown Allele origin: germline	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000925128.1 First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019	Comment: 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, … (more) 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. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001963098.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Aug 05, 2020)	no assertion criteria provided Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002086388.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Pathogenic (Oct 30, 2023)	no assertion criteria provided Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004099452.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023
not provided (-)	no classification provided (in vitro) Method: in vitro	not provided Affected status: not applicable Allele origin: not applicable	Dept. of Genetics and Pharmacogenomics, Merck Research Labs Accession: SCV000189623.1 First in ClinVar: Feb 28, 2015 Last updated: Feb 28, 2015 Comment: In vitro functional profiling of LDL-receptor missense alleles identified through large-scale association testing	Publications: PubMed (1) PubMed: 25647241
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Comment:

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.

Comment:

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.

Comment:

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, BrÃ¦nne 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, TichÃ½ 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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
unknown functional consequence	Method not provided	Result not provided	Dept. of Genetics and Pharmacogenomics, Merck Research Labs Accession: SCV000189623.1	Publications PubMed (1) Comment: unclear

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identification of New Genetic Determinants in Pediatric Patients with Familial Hypercholesterolemia Using a Custom NGS Panel.	Rutkowska L	Genes	2022	PMID: 35741760
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.	Sturm AC	JAMA cardiology	2021	PMID: 34037665
Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020.	Leren TP	Atherosclerosis	2021	PMID: 33740630
The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia.	Meshkov A	Genes	2021	PMID: 33418990
Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing.	Miroshnikova VV	Biomedical reports	2021	PMID: 33269076
Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia.	Rieck L	Clinical genetics	2020	PMID: 32770674
Population genetic screening efficiently identifies carriers of autosomal dominant diseases.	Grzymski JJ	Nature medicine	2020	PMID: 32719484
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias.	Dron JS	BMC medical genomics	2020	PMID: 32041611
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: agibbs@bcm.edu	American journal of human genetics	2019	PMID: 31447099
Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.	Trinder M	Journal of the American College of Cardiology	2019	PMID: 31345425
The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hypercholesterolemia (GoTCHA) study.	Luirink IK	Journal of clinical lipidology	2019	PMID: 30795984
Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis.	Chora JR	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29261184
Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease.	Lu X	Nature genetics	2017	PMID: 29083407
The genetic spectrum of familial hypercholesterolemia in the central south region of China.	Xiang R	Atherosclerosis	2017	PMID: 28235710
The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey.	Gabčová D	Physiological research	2017	PMID: 27824480
Clinical characterization and mutation spectrum of German patients with familial hypercholesterolemia.	Grenkowitz T	Atherosclerosis	2016	PMID: 27596133
The genetic spectrum of familial hypercholesterolemia in south-eastern Poland.	Sharifi M	Metabolism: clinical and experimental	2016	PMID: 26892515
Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction.	Brænne I	European journal of human genetics : EJHG	2016	PMID: 26036859
Molecular-genetic aspects of familial hypercholesterolemia.	Gabcova-Balaziova D	Endocrine regulations	2015	PMID: 26238499
Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.	Thormaehlen AS	PLoS genetics	2015	PMID: 25647241
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.	Do R	Nature	2015	PMID: 25487149
Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.	Lange LA	American journal of human genetics	2014	PMID: 24507775
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.	Bertolini S	Atherosclerosis	2013	PMID: 23375686
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.	Tichý L	Atherosclerosis	2012	PMID: 22698793
An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia.	Dušková L	Atherosclerosis	2011	PMID: 21310417
Genomic characterization of large rearrangements of the LDLR gene in Czech patients with familial hypercholesterolemia.	Goldmann R	BMC medical genetics	2010	PMID: 20663204
Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.	Chmara M	Journal of applied genetics	2010	PMID: 20145306
Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.	Brusgaard K	Clinical genetics	2006	PMID: 16542394
Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.	Leren TP	Seminars in vascular medicine	2004	PMID: 15199436
Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population.	Yu W	Atherosclerosis	2002	PMID: 12417285
Spectrum of low density lipoprotein receptor mutations in Czech hypercholesterolemic patients.	Kuhrová V	Human mutation	2002	PMID: 11754108
The molecular basis of familial hypercholesterolemia in The Netherlands.	Fouchier SW	Human genetics	2001	PMID: 11810272
Mutations in the low-density-lipoprotein receptor gene in German patients with familial hypercholesterolaemia.	Weiss N	Journal of inherited metabolic disease	2000	PMID: 11196104
Familial hypercholesterolemia in Austria reflects the multi-ethnic origin of our country.	Schmidt H	Atherosclerosis	2000	PMID: 10657581
Racial differences in the frequencies of scleroderma-related autoantibodies.	Reveille JD	Arthritis and rheumatism	1992	PMID: 1734910
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.	Hobbs HH	Human mutation	1992	PMID: 1301956
The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.	Hobbs HH	Annual review of genetics	1990	PMID: 2088165
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/da36a90c-1718-424e-83fa-5e42e5af70fa	-	-	-	-
https://www.ncbi.nlm.nih.gov/clinvar/variation/161287/?new_evidence=false	-	-	-	-
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Text-mined citations for rs139043155 ...

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Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs139043155 ...