rs139043155
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PS3_ModeratePP4PP1_StrongPS4PM5_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
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.798T>A | p.Asp266Glu | missense_variant | Exon 5 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251482Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135918
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29AN XY: 727238
GnomAD4 genome 0.0000394 AC: 6AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74368
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:23Benign:1
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Criteria applied: PS4,PM5_STR,PP1_STR,PS3_MOD,PM2 -
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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. -
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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 -
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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 -
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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. -
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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. -
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. -
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not provided Pathogenic:8Other:1
LDLR: PS4, PM1, PM5, PP4:Moderate, PM2:Supporting, PS3:Supporting -
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) -
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. -
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PP1_strong, PP4, PM2_moderate, PM5_strong, PS3, PS4_moderate -
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. -
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Familial hypercholesterolemia Pathogenic:5Uncertain:1
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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. -
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. -
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. -
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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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Asp245Glu. ClinVar contains an entry for this variant (Variation ID: 161287). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Homozygous familial hypercholesterolemia Pathogenic:1
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
ACMG categories: PS1,PS4,PM2,PP5,BP1 -
Cardiovascular phenotype Pathogenic:1
The p.D266E pathogenic mutation (also known as c.798T>A), located in coding exon 5 of the LDLR gene, results from a T to A substitution at nucleotide position 798. The aspartic acid at codon 266 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration (also referred to as D245E) has been described in multiple individuals from familial hypercholesterolemia (FH) cohorts, and reduced LDL-R activity was reported in patients' cultured fibroblasts (Hobbs HH et al. Hum. Mutat.1992;1:445-66, Schmidt H et al. Atherosclerosis 2000;148:431-2, Fouchier SW et al. Hum. Genet. 2001;109:602-15, Brusgaard K et al. Clin. Genet. 2006;69:277-83). Other variants at the same codon (p.D266G (c.797A>G), p.D266Y (c.796G>T), and p.D266H (c.796G>C)) have been also been reported in association with FH (Weiss N et al. J. Inherit. Metab. Dis., 2000 Dec;23:778-90; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Xiang R et al. Atherosclerosis, 2017 Mar;258:84-88). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Hypercholesterolemia Uncertain:1
Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at