rs200727689
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.502G>A(p.Asp168Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D168E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.502G>A | p.Asp168Asn | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.502G>A | p.Asp168Asn | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251288Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135884
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461684Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34AN XY: 727148
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:12
Pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Apr 04, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 06, 2021 | - - |
Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Mar 10, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
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 = 3 , family member = 1 with co-segregation / FH-Sephardic, 2 to 5% LDLR Activity / Software predictions: Conflicting - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 24, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 05, 2022 | - - |
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.Asp147Asn in the mature protein) replaces aspartic acid with asparagine at codon 168 in the fourth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDL binding and uptake, although effect is not as severe as null alleles (PMID: 25545329, 25647241). This variant has been reported in over ten individuals and families affected with familial hypercholesterolemia (PMID: 15556094, 16205024, 16389549, 17955342, 22859806, 23669246, 27784735, 28379029, 33807407, 34037665; Color internal data), including a homozygous individual with severe phenotype (PMID: 27784735). This variant has been identified in 2/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Asp168His, p.Asp168Gly, p.Asp168Tyr) are known to be disease-causing (ClinVar variation ID: 251258, 251260, 251259), indicating that aspartic acid at this position is important for LDLR function. Based on available evidence, this variant is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
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 | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The LDLR c.502G>A (p.D168N) variant has been previously reported in the heterozygous state in autosomal dominant familial hypercholesterolemia (PMID: 9259195; 9678702; 12124988; 15556094; 19007590; 25545329; 25647241). - |
Familial hypercholesterolemia Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 02, 2020 | Variant summary: LDLR c.502G>A (p.Asp168Asn) results in a conservative amino acid change located in the LDLR ligand binding domain (R4) (Etxebarria_2015) of 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 8e-06 in 251288 control chromosomes (gnomAD). c.502G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Taylor_2010, Rall_2014, Sanchez-Hernandez_2016, Wald-2016). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in an impaired LDL binding capacity of WT. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (4x). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Feb 04, 2021 | The c.502G>A (p.Asp168Asn) variant in the LDLR gene is located on the exon 4 and is predicted to replace aspartic acid with asparagine at codon 168 (p.Asp168Asn). The variant has been reported in more than 10 unrelated individuals affected with familial hypercholesterolemia (PMID: 33807407, 32522009, 27783906, 27784735, 28379029, 22859806, 19007590, 16389549, 16205024, 9678702, 30293936). The p.Asp168Asn variant is located in the well-established functional domain (amino acids 105-232) critical to the protein function. Experimental study in the LDLR deficient cell line proved the negative functional impact of this variant and defective LDL binding (<70%) (PMID: 25545329). The variant has been reported in ClinVar (ID: 183136). This variant is rare in the general population according to gnomAD (2/251288). Computational prediction algorithms suggest a deleterious impact (REVEL score 0.78). Therefore, the c.502G>A (p.Asp168Asn) variant of LDLR has been classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 01, 2023 | This missense variant (also known as p.Asp147Asn in the mature protein) replaces aspartic acid with asparagine at codon 168 in the fourth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDL binding and uptake, although effect is not as severe as null alleles (PMID: 25545329, 25647241). This variant has been reported in over ten individuals and families affected with familial hypercholesterolemia (PMID: 15556094, 16205024, 16389549, 17955342, 22859806, 23669246, 27784735, 28379029, 33807407, 34037665; Color internal data), including a homozygous individual with severe phenotype (PMID: 27784735). This variant has been identified in 2/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Asp168His, p.Asp168Gly, p.Asp168Tyr) are known to be disease-causing (ClinVar variation ID: 251258, 251260, 251259), indicating that aspartic acid at this position is important for LDLR function. Based on available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 168 of the LDLR protein (p.Asp168Asn). This variant is present in population databases (rs200727689, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9259195, 9678702, 12124988, 15556094, 16205024, 19007590, 22859806, 27784735). This variant is also known as p.Asp147Asn. ClinVar contains an entry for this variant (Variation ID: 183136). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25545329, 25647241). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 11, 2020 | - - |
not provided Pathogenic:1Other:1
not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2022 | Published functional studies demonstrate decreased receptor binding and LDL uptake compared to wild type protein (Etxebarria et al., 2015; Thormaehlen et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Also known as D147N; This variant is associated with the following publications: (PMID: 9259195, 30617148, 15556094, 16205024, 31447099, 25487149, 9678702, 12124988, 19007590, 25647241, 22859806, 27784735, 29874871, 28379029, 23669246, 32522009, 33807407, 32853555, 32719484, 33740630, 34037665, 33087929, 2988123, 12459547, 25545329) - |
Homozygous familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 07, 2021 | The p.Asp168Asn variant in LDLR has been reported in the heterozygous state in at least 12 individuals (11 heterozygotes, 1 homozygote) with familial hypercholesterolemia (FH), and in 2 individuals with early-onset myocardial infarction and segregated with FH in one affected relative (Day 1997 PMID: 9259195, Lee 1998 PMID: 9678702, Punzalan 2005 PMID: 16205024, Taylor 2010 PMID: 20236128, Do 2015 PMID: 25487149, Wald 2016 PMID: 27783906, Sanchez-Hernandez 2016 PMID: 27784735). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183136) and has been identified in 0.002% (2/113632) European chromosomes by the gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Asp168Asn variant may cause a decrease in LDL uptake and binding (Etxebarria 2015 PMID: 25545329) and computational prediction tools and conservation analyses are consistent with pathogenicity. Additionally, other variants at this position (p.Asp168His, p.Asp168Gly, p.Asp168Gln) have been reported in association with FH by multiple clinical laboratories in ClinVar. In summary, the p.Asp168Asn variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PS3_Moderate, PM1, PM2_Supporting, PP3, PM5_Supporting. - |
LDLR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 13, 2023 | The LDLR c.502G>A variant is predicted to result in the amino acid substitution p.Asp168Asn. This variant is alternatively referred to as p.Asp147Asn using Legacy nomenclature. This variant and other similar variants affecting amino acid Asp168 have been reported in several unrelated patients with hypercholesterolemia (Day et al. 1997 PubMed ID: 9259195; Lee et al. 1998 PubMed ID: 9678702; Punzalan et al. 2005 PubMed ID: 16205024; Civiera et al. 2008 PubMed ID: 19007590; Etxebarria et al. 2015 PubMed ID: 25545329). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11216084-G-A) and is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183136/). This variant is interpreted as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 20, 2024 | The p.D168N variant (also known as c.502G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 502. The aspartic acid at codon 168 is replaced by asparagine, an amino acid with highly similar properties, and is located in the ligand binding region of the protein. This alteration (also referred to as D147N) has been detected in individuals from multiple familial hypercholesterolemia cohorts and in an an individual with mixed hyperlipidemia (Day IN et al. Hum Mutat. 1997;10:116-27; Lee WK et al. J Med Genet. 1998;35:573-8; Laurie AD et al. Atheroscler Suppl. 2004;5(5):13-5;Civeira F et al. J Am Coll Cardiol. 2008; Futema M et al. Atherosclerosis. 2013;229:161-8; Raal FJ et al. Lancet. 2015;385(9965):341-50; Sánchez-Hernández RM et al. Circ Cardiovasc Genet. 2016;9(6):504-510). This variant has been reported to result in reduced LDL binding and uptake in vitro (Etxebarria A et al. Atherosclerosis. 2015 Feb;238(2):304-12; Thormaehlen AS et al. PLoS Genet. 2015;11(2):e1004855). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at