rs376459828
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.590G>A(p.Cys197Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,898 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. C197F) 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.590G>A | p.Cys197Tyr | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.590G>A | p.Cys197Tyr | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152246Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461652Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727146
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74376
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:12
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 06, 2019 | - - |
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 /FH-El-Savador, <2% activy LDLR / Software predictions: Damaging - |
Likely pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 01, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 10, 2024 | This missense variant is located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys176Tyr in the mature protein sequence and as FH El Salvador-1 in the literature. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Cells from an individual compound heterozygous for this variant and p.Gln678\* showed <2% LDLR activity (PMID: 1301956). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 18096825, 20538126, 21376320, 23064986, 27765764, 27816806, 28502495, 32044282, 37119068). This variant has been reported in five heterozygous and two homozygous individuals from a family affected with familial hypercholesterolemia, with the two homozygotes having coronary artery disease and myocardial infarction (PMID: 27816806). It has also been reported in homozygous state in an individual affected with severe homozygous familial hypercholesterolemia (PMID: 34029164). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Cys197Gly, p.Cys197Phe, and p.Cys197Trp) are known to be disease-causing (ClinVar variation ID: 251308, 251309, 251311), indicating that cysteine at this position is important for LDLR function. Based on the available evidence, this variant is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jul 12, 2023 | The c.590G>A variant in LDLR has been reported in many individuals with hypercholesterolemia (also known as El Salvador type) in both heterozygous and biallelic states [PMID: 1301956, 27816806, 34040191, 33740630, 34037665, 33994402] and deposited in ClinVar [ClinVar ID: 200919] as Pathogenic by multiple submitters. The c.590G>A variant is observed in 14 alleles (~0.0033% minor allele frequency with 0 homozygotes) in population databases (gnomAD v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.590G>A variant in LDLR is located in exon 4 of this 18-exon gene, and is predicted to replace an evolutionarily conserved cysteine amino acid with tyrosine at position 197 in the LDL-receptor class A repeat 5 (aa195-233) region of the encoded protein [UniProt ID: P01130]. In silico predictions are in favor of damaging effect for the p.(Cys197Tyr) variant [(CADD v1.6 = 24.3, REVEL = 0.936)]. The LDL receptor activity was found less than 2% in an individual with hypercholesterolemia carrying this variant with a stop-gain variant [PMID: 1301956]. Other variants affecting the p.Cys197 residue have also been reported in individuals with hypercholesterolemia [PMID: 28349240]. Based on available evidence this c.590G>A p.(Cys197Tyr) variant identified in LDLR is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 14, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 19, 2023 | The LDLR c.590G>A (p.Cys197Tyr) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 1301956 (1992), 18096825 (2008), 19717150 (2010), 20538126 (2010), 21276076 (2011), 23064986 (2012), 27816806 (2016), 27765764 (2016), 28502495 (2017), 34037665 (2021), and 33994402 (2021)). Experimental studies have shown that this variant has a damaging effect on protein folding, maturation, and finally results in reduced LDLR activity (PMIDs: 1301956 (1992) and 14993243 (2004)). The frequency of this variant in the general population, 0.000032 (1/31400 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 20, 2019 | PS3_moderate, PS4, PM1, PM2, PM5, PP3 - |
Familial hypercholesterolemia Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 04, 2019 | Variant summary: LDLR c.590G>A (p.Cys197Tyr), also known as FH-El Salvador-1, results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat domain (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246122 control chromosomes. c.590G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Hobbs_1992; Ahmad_2012; Junyent_2010; Setia_2016; Chious_2011; Martin-Campos_2018). 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. The most pronounced variant effect results in <2% of normal LDLR activity (Hobbs_1992). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. 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 | Aug 09, 2021 | The c.590G>A (p.Cys197Tyr) variant, also known as p.Cys176Tyr in LDLR gene that encodes for low density lipoprotein receptor, has been identified in at least ten individuals affected with familial hypercholesterolemia (FH) (PMID: 18096825, 20538126, 21376320, 23064986, 27765764, 28502495, 32044282, 21276076, 33994402, 30293936). This variant has also been observed in homozygous status in two individuals in a family with coronary artery disease (PMID: 27816806), and five individuals with homozygous FH (PMID: 37119068, 27365335). Fibroblasts derived from an individual harboring this variant in compound heterozygous status (with p.Gln678*) revealed <2% LDLR activity (PMID: 1301956). This variant lies in the well-established LDL binding domain (amino acids 105-232) critical for protein function and affects the Cysteine residue essential for disulfide bond formation (PMID: 2600087). In-silico computational prediction tools suggest that the p.Cys197Tyr variant may have deleterious effect on the protein function (REVEL score: 0.936). This variant is found to be rare (1/31400; 0.00003185) in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 200919). Therefore, the c.590G>A (p.Cys197Tyr) variant in LDLR gene is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 08, 2023 | This missense variant is located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys176Tyr in the mature protein sequence and as FH El Salvador-1 in the literature. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Cells from an individual compound heterozygous for this variant and p.Gln678\* showed <2% LDLR activity (PMID: 1301956). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 18096825, 20538126, 21376320, 23064986, 27765764, 27816806, 28502495, 32044282, 37119068). This variant has been reported in five heterozygous and two homozygous individuals from a family affected with familial hypercholesterolemia, with the two homozygotes having coronary artery disease and myocardial infarction (PMID: 27816806). It has also been reported in homozygous state in an individual affected with severe homozygous familial hypercholesterolemia (PMID: 34029164). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Cys197Gly, p.Cys197Phe, and p.Cys197Trp) are known to be disease-causing (ClinVar variation ID: 251308, 251309, 251311), indicating that cysteine at this position is important for LDLR function. Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 197 of the LDLR protein (p.Cys197Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 18096825, 20538126, 21276076, 23064986, 27765764, 27816806). This variant is also known as p.Cys176Tyr. ClinVar contains an entry for this variant (Variation ID: 200919). 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 affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic. - |
Homozygous familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 17, 2021 | The p.Cys197Tyr variant in LDLR has been reported in the heterozygous, compound heterozygous, or homozygous state in at least 10 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 2 affected individuals from 2 families (Hobbs 1992 PMID: 1301956, Setia 2016 PMID: 27816806, Chiou 2010 PMID: 20538126, Junyent 2008 PMID: 18096825, Ahmad 2012 PMID: 23064986, Wang 2016 PMID: 27765764, Khera 2019 PMID: 30586733, Setia 2020 PMID: 32044282, Dron 2020 PMID: 32041611, Orringer 2020 PMID 32505727, LMM data). It has also been identified in 0.01% (2/15282) of Latino chromosomes in gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 200919). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies also support that this variant impacts protein function (Hobbs 1992 PMID: 1301956). This variant occurs in a critical cysteine residue involved in disulfide bond formation, where the majority of pathogenic variants in this gene have been identified. Additional variants involving this codon (p.Cys197Gly, p.Cys197Phe, p.Cys197Trp) have been identified in individuals with FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PM1, PM3, PM5, PM2_Supporting, PP3. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 01, 2021 | The p.C197Y pathogenic mutation (also known as c.590G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 590. The cysteine at codon 197, located in LDLR class A repeat 5, is replaced by tyrosine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular alteration, also referred to as FH El Salvador-1 or C176Y, has been reported in individuals with FH and has demonstrated reduced LDLR activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Junyent M et al. Atherosclerosis, 2010 Feb;208:437-41; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Martinez M et al. Am J Cardiol, 2016 08;118:504-10; Setia N et al. Atherosclerosis, 2016 Dec;255:31-36; Martín-Campos JM et al. J Clin Lipidol 2018 Oct;12:1452-1462). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 5. In addition, alterations affecting the same amino acid (C197F, C197W, C197G, C197R) have also been described in FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Chmara M et al. J Appl Genet. 2010;51(1):95-106; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at