rs875989906
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.661G>A(p.Asp221Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,459,316 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. D221G) has been classified as 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.661G>A | p.Asp221Asn | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.661G>A | p.Asp221Asn | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000617 AC: 9AN: 1459316Hom.: 0 Cov.: 33 AF XY: 0.00000689 AC XY: 5AN XY: 725566
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:9
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jun 05, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | Asp221 bind structural Ca2+. - |
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jun 27, 2008 | - - |
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 | subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH / Software predictions: Conflicting - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 04, 2023 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 16, 2023 | This missense variant (also known as p.Asp200Asn in the mature protein) replaces aspartic acid with asparagine at codon 221 in the LDLR type A repeat 5 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). Experimental functional studies have shown that this variant may disrupt LDLR protein folding due to defective calcium ion binding (PMID: 8784348, 9262405) and result in reduced LDLR activity (PMID: 9409298). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 9409298, 10090484, 11196104, 16250003, 17094996, 24075752, 25962062, 29399563, 33740630, 34456200). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants affecting the same codon (p.Asp221Gly, p.Asp221Tyr, Asp221Val) are considered to be disease-causing (ClinVar variation ID: 183092, 251356, 251357), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 05, 2024 | Criteria applied: PS4,PM5_STR,PM2_SUP,PP3 - |
Familial hypercholesterolemia Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 30, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 12, 2018 | The c.661G>A (p.Asp221Asn) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 9409298, 10090484, 11196104, 15199436, 15359125, 16250003, 17094996, 24075752, 25962062). The variant is not observed in gnomAD. The allelic change p.Asp221Tyr is an established pathogenic variant for FH. Functional studies demonstrated deleterious effect of the p.Asp221Asn variant. Multiple algorithms predicted this change to be deleterious. Therefore, the c.661G>A (p.Asp221Asn) variant in the LDLR gene is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 221 of the LDLR protein (p.Asp221Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1714262, 11196104, 17094996, 24075752, 25962062). This variant is also known as c.661G>A, p.Asp200Asn. ClinVar contains an entry for this variant (Variation ID: 226331). 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.Asp221 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 19318025, 23375686, 25487149, 25647241). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 12, 2023 | This missense variant (also known as p.Asp200Asn in the mature protein) replaces aspartic acid with asparagine at codon 221 in the LDLR type A repeat 5 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). Experimental functional studies have shown that this variant may disrupt LDLR protein folding due to defective calcium ion binding (PMID: 8784348, 9262405) and result in reduced LDLR activity (PMID: 9409298). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 9409298, 10090484, 11196104, 16250003, 17094996, 24075752, 25962062, 29399563, 33740630, 34456200). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants affecting the same codon (p.Asp221Gly, p.Asp221Tyr, Asp221Val) are considered to be disease-causing (ClinVar variation ID: 183092, 251356, 251357), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 25, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Located in a region intolerant to change; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22883975, 31447099, 16250003, 10090484, 11196104, 15359125, 19837725, 24075752, 35913489, 9544745, 33955087, 33740630, 32719484, 34037665) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 20, 2023 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple in individuals with familial hypercholesterolemia (FH) (PMID: 9409298 (1997), 9544745 (1998), 11196104 (2000), 34456200 (2021)), including one homozygous individual (PMID: 17142622 (2006)). It has also been reported in an individual with autosomal dominant hypercholesterolemia (ADH) (PMID: 16250003 (2005)), as well as in an otherwise healthy individual (PMID: 32719484 (2020)). A functional study found this variant was damaging to protein function (PMID: 9409298 (1997)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2022 | The p.D221N variant (also known as c.661G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 661. The aspartic acid at codon 221 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in a number of individuals with familial hypercholesterolemia (Sun XM et al. Atherosclerosis, 1998 Jan;136:175-85; Ebhardt M et al. Hum. Mutat., 1999;13:257; Kim JH et al. Mol. Cells, 2004 Aug;18:63-70; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6). This alteration has also been reported as homozygous in a subject with tendom xanthomas and a total cholesterol of >500 mg/dL (Græsdal A et al. J Clin Lipidol Mar;6:331-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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