NM_000527.5:c.1720C>T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PS4_SupportingPP3PP4BS3_Supporting
This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_supporting and BS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001384 (0.01384%) in Other populations exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.967.PP4 - Variant meets PM2. Variant identified in 5 FH cases (1 case with Simon-Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID:11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID:29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register possible/definite published in PMID:26892515.PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case with Simon-Broome from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID:11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID:29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register criteria published in PMID:26892515.BS3_supporting - PMID:25647241: Level 3 assay- study on HeLa-Kyoto cells, LDLR-GFP construct, WB + CLSM assays, whole cycle is above 100% of wild-type activity.- functional study is consistent with no damaging effect. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023561/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1720C>T | p.Arg574Cys | missense_variant | Exon 12 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152128Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251482Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135916
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461660Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14AN XY: 727122
GnomAD4 genome 0.0000328 AC: 5AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74434
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4Uncertain:4
The p.Arg574Cys variant in LDLR has been reported in 14 individuals with familial hypercholesterolemia (PMID: 29290422, 25647241, 22698793, 20145306, 25487149, 23375686, 11462246, 26892515, 19446849), and has been identified in 0.006% (8/129194) European non-Finnish chromosomes. 0.004% (1/25116) European Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs185098634). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS, likely pathogenic, and pathogenic(Variation ID#: 183123). 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 summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PM2_supporting, PP3 (Richards 2015). -
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NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_supporting and BS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001384 (0.01384%) in Other populations exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.967. PP4 - Variant meets PM2. Variant identified in 5 FH cases (1 case with Simon-Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register possible/definite published in PMID: 26892515. PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case with Simon-Broome from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register criteria published in PMID: 26892515. BS3_supporting - PMID: 25647241: Level 3 assay - study on HeLa-Kyoto cells, LDLR-GFP construct, WB + CLSM assays, whole cycle is above 100% of wild-type activity. - functional study is consistent with no damaging effect. -
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subject mutated among 2600 FH index cases screened = 1, family member=1 /FH-Germany/software prediction damaging -
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This missense variant replaces arginine with cysteine at codon 574 of the LDLR protein. This variant is also known as p.Arg553Cys in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the LDLR protein (a.a. 572-615), where pathogenic missense variants are found enriched (ClinVar-LDLR). 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 high-throughput experimental study has shown that this variant may not disrupt LDLR function (PMID: 25647241). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11462246, 15823288, 19318025, 19446849, 26892515, 27050191, 30293936, 34297352). This variant has been stated to segregate with disease in a German family, although detailed data from the family study has not been provided (PMID: 11462246). This variant has been identified in 10/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg574His, is considered to be disease-causing (ClinVar variation ID: 251996), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
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Familial hypercholesterolemia Pathogenic:2
This missense variant replaces arginine with cysteine at codon 574 of the LDLR protein. This variant is also known as p.Arg553Cys in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the LDLR protein (a.a. 572-615), where pathogenic missense variants are found enriched (ClinVar-LDLR). 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 high-throughput experimental study has shown that this variant may not disrupt LDLR function (PMID: 25647241). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11462246, 15823288, 19318025, 19446849, 26892515, 27050191, 30293936, 34297352). This variant has been stated to segregate with disease in a German family, although detailed data from the family study has not been provided (PMID: 11462246). This variant has been identified in 10/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg574His, is considered to be disease-causing (ClinVar variation ID: 251996), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 574 of the LDLR protein (p.Arg574Cys). This variant is present in population databases (rs185098634, gnomAD 0.005%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11462246, 19446849, 20145306, 23375686, 25487149, 26892515). ClinVar contains an entry for this variant (Variation ID: 183123). 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.Arg574 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20018285, 22698793, 28028493). 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. -
not provided Pathogenic:1Other:1
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Cardiovascular phenotype Pathogenic:1
The p.R574C variant (also known as c.1720C>T), located in coding exon 12 of the LDLR gene, results from a C to T substitution at nucleotide position 1720. The arginine at codon 574 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in at least five individuals meeting clinical criteria for familial hypercholesterolemia (FH) as well as once in a cohort of individuals who experienced a myocardial infarction (MI) event before age 50 (Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Nauck MS et al. Hum. Mutat., 2001 Aug;18:165-6). In addition, a different alteration located at the same position, p.R574S, has been detected in multiple individuals meeting clinical criteria for familial hypercholesterolemia (FH) (Paththinige CS et al. Lipids Health Dis, 2018 May;17:100; Du R et al. Springerplus, 2016 Dec;5:2095; Xiang R et al. Atherosclerosis, 2017 03;258:84-88); Ma Y et al. J Clin Lipidol Oct;12:230-235.e6). 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 majority of available evidence to date, this variant is likely to be pathogenic. -
not specified Uncertain:1
Variant summary: LDLR c.1720C>T (p.Arg574Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five 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 (gnomAD). c.1720C>T has been reported in the literature in many individuals affected with Hypercholesterolemia, primarily in settings of gene or multigene panel testing in large cohorts of patients and in some cases their relatives, but without strong documented evidence of segregation (e.g. Nauck_2001, Damgaard_2005, Bertolini_2013, Trinder_2020, Leren_2021, Noto_2022). These data suggest the variant may be associated with Familial Hypercholesterolemia but do not allow for unequivocal conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function in a high-throughput in vitro system and found no damaging effect of this variant (e.g. Thormaehlen_2015). Ten submitters, including the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The variant has been classified as either pathogenic (n=1)/likely pathogenic (n=5) or VUS (n=4, including the ClinGen Expert Panel). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at