rs121908039
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3PS4PP1_StrongPM1PM2PP4PP3
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PS4, PP1_Strong, PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 January 2022. The supporting evidence is as follows:PM2 - PopMax MAF = 0.00019 (0.019%) in European Non-Finnish genomes (gnomAD v2.1.1).PP3 - REVEL = 0.85, which is above the threshold of 0.75.PM1 - variant meets PM2 and is located in exon 4.PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: Result of normal cell surface LDLR (100%), 4% LDL binding and 18% LDL uptake, compared to wild-type (PMID:34167030).PS4 - Variant meets PM2 and is identified in at least 22 unrelated index cases who fulfill clinical criteria for FH (8 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN criteria from Robarts Research Institute; 5 cases with DLCN criteria from PathWest Laboratory Medicine WA; 2 cases with DLCN criteria from Color; 1 case with MEDPED criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory).PP1_Strong - Variant segregates with phenotype in 14 informative meioses from 8 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 4 families: 8 relatives affected with the variant and 1 relative unaffected without the variant; Robarts Research Institute – 2 families: 2 relatives affected with the variant; PathWest Laboratory Medicine WA – 2 families: 2 affected relative with the variant and 1 unaffected relative without the variant)PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023721/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
Publications
- hypercholesterolemia, familial, 1Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
- homozygous familial hypercholesterolemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.551G>A | p.Cys184Tyr | missense_variant | Exon 4 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152232Hom.: 0 Cov.: 33 show subpopulations
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461722Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727174 show subpopulations
Age Distribution
GnomAD4 genome 0.0000197 AC: 3AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74378 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:17
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subjects mutated among 2600 FH index cases screened = 2 /FH-Rome-2 / Software predictions: Damaging -
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This missense variant (also known as p.Cys163Tyr in the mature protein) replaces cysteine with tyrosine at codon 184 in the fourth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). 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 in transfected CHO-ldlA7 cells has shown that this variant causes a significant reduction in LDL binding and uptake (PMID: 34167030). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (11668627, 19843101, 20236128, 20828696, 31345425, 32331935, 34037665, 34297352; Color internal data). It has been shown that this variant segregates with disease in over 10 affected individuals across 3 families (PMID: 9678702). This variant has been identified in 3/31402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys184Arg, is considered to be disease-causing (ClinVar variation ID: 251294), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
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0/190 non-FH alleles; 0/100 healthy control individuals -
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This c.551G>A (p.Cys184Tyr) variant in the LDLR gene has been reported to segregate with familial hypercholesterolemia in several families (PMID: 9678702) and has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID: 10559517, 11668627, 17765246, 20236128) and is rarely detected in the general population. Cysteine residue at position 184 of the LDLR protein is highly evolutionarily conserved. Based on this information, the c.551G>A (p.Cys184Tyr) variant in the LDLR gene is classified as likely pathogenic. -
The NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PS4, PP1_Strong, PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 January 2022. The supporting evidence is as follows: PM2 - PopMax MAF = 0.00019 (0.019%) in European Non-Finnish genomes (gnomAD v2.1.1). PP3 - REVEL = 0.85, which is above the threshold of 0.75. PM1 - variant meets PM2 and is located in exon 4. PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: Result of normal cell surface LDLR (100%), 4% LDL binding and 18% LDL uptake, compared to wild-type (PMID: 34167030). PS4 - Variant meets PM2 and is identified in at least 22 unrelated index cases who fulfill clinical criteria for FH (8 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN criteria from Robarts Research Institute; 5 cases with DLCN criteria from PathWest Laboratory Medicine WA; 2 cases with DLCN criteria from Color; 1 case with MEDPED criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory). PP1_Strong - Variant segregates with phenotype in 14 informative meioses from 8 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 4 families: 8 relatives affected with the variant and 1 relative unaffected without the variant; Robarts Research Institute – 2 families: 2 relatives affected with the variant; PathWest Laboratory Medicine WA – 2 families: 2 affected relative with the variant and 1 unaffected relative without the variant) PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. -
Familial hypercholesterolemia Pathogenic:6
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This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 184 of the LDLR protein (p.Cys184Tyr). This variant is present in population databases (rs121908039, gnomAD 0.02%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9678702, 11668627, 20236128, 20828696, 25461735). It has also been observed to segregate with disease in related individuals. 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.Cys163Tyr. ClinVar contains an entry for this variant (Variation ID: 3739). 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 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. -
The c.551G>A variant in the LDLR gene replaces cysteine with tyrosine at codon 184 of the LDLR protein (p.Cys184Tyr). It has been reported to segregate with familial hypercholesterolemia in several families (PMID: 9678702) and has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID: 10559517, 11668627, 17765246, 20236128). This variant is observed at an ultra-low frequency in the general population (gnomAD database 3/31402) and reported to be damaging by multiple bioinformatics algorithms. This variant affects a cysteine residue located in the fourth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant was identified in a patient with familial hypercholesterolemia. Functional studies demonstrated reduced LDLR activity in fibroblasts derived from this patient. Based on this information, the c.551G>A (p.Cys184Tyr) variant in the LDLR gene is classified as pathogenic. -
The LDLR c.551G>A p.(Cys184Tyr) variant has been seen in >=10 FH patients meeting clinical criteria, including after alternative causes of high cholesterol were excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 9678702, 11668627, 19843101, 20236128, 20828696, 32331935, 34167030, ClinGen FH VCEP data, internal data). Variant segregates with FH phenotype in >= 6 informative meioses from multiple families (PP1_STRONG; PMIDs 9678702, 34167030, ClinGen FH VCEP data). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001944 in European (non-Finnish) population, which is lower than the ClinGen FH VCEP threshold (=<0.0002), so PM2_MODERATE is met. This is a missense change of a highly conserved cysteine residue and meets PM2 (PM1_MODERATE). Level 1 functional assay showed reduced LDL binding and uptake <20% (PS3_STRONG; PMID 34167030) and the REVEL score is 0.854 (PP3_SUPPORTING). Based on the evidence listed above, we have classified this variant as Pathogenic. -
Variant summary: The LDLR c.551G>A (p.Cys184Tyr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Cys184 is located in repeat 4 of the LDLR class A (cyteine-rich) repeat, and Cys184 is highly conserved across species. In LDL receptors, the class A domains form the binding site for LDL and calcium, and numerous familial hypercholestorolemia pathogenic LDLR variants alter the calcium coordinating residue of LDL-A domains.This variant was absent in 121144 control chromosomes, but has been cited in many FH families in the literature and has been shown to co-segregate with disease in multiple independent families (Lee_JMG_1998). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a commonly known FH-causing LDLR variant and was classified as Pathogenic. -
This missense variant replaces cysteine with tyrosine at codon 184 in the fourth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant is also known as p.Cys163Tyr in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). 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 has shown that this variant causes a significant reduction in LDL binding and uptake (PMID: 34167030). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 11668627, 19843101, 20236128, 20828696, 31345425, 32331935, 34037665, 34297352; Color internal data). It has been shown that this variant segregates with disease in over 10 affected individuals across 3 families (PMID: 9678702). This variant has been identified in 3/31402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys184Arg, is reported to be disease-causing (ClinVar variation ID: 251294), indicating that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
not provided Pathogenic:3Other:1
Variant interpreted as Pathogenic and reported on 11-12-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies show that LDL-deficient CHO-ldlA7 cells transfected with the p.(C184Y)-LDL demonstrates impaired binding activity (PMID: 34167030); Also reported as FH Rome-2 and p.(C163Y) due to alternate nomenclature; This variant is associated with the following publications: (PMID: 31447099, 30586733, 9678702, 10559517, 11668627, 11810272, 20236128, 20828696, 25461735, 28873201, 33303402, 32719484, 32331935, 33740630, 33418990, 34037665, 27765764, 34363016, 22883975, 1301956, 32041611, 27680772, 31345425, 34297352, 24627126, 30583242, 34906454, 34167030) -
The LDLR c.551G>A (p.Cys184Tyr) variant (also known as C163Y) in the LDLR gene. In the published literature, this variant has been reported in multiple individuals/families with familial hypercholesterolemia (PMIDs: 33740630 (2021), 33418990 (2021), 32331935 (2020), 32143996 (2020), 28873201 (2017), 27765764 (2016), 25461735 (2015), 23375686 (2013), 22883975 (2012), 20236128 (2010), 17765246 (2008), 11810272 (2001), 11668627 (2001), 10357843 (1999)), and early-onset myocardial infarction (PMID: 30586733 (2019)). Functional studies indicate this variant causes significantly reduced LDLR binding and LDL uptake activity in vivo (PMID: 30167030 (2021)). The frequency of this variant in the general population, 0.00019 (3/15432 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. -
The LDLR c.551G>A; p.Cys184Tyr variant (rs121908039) is reported in the literature in 15 individuals affected with high LDL-C (Sturm 2021). Moreover, this variant has been identified as a recurrent co-segregating allele within three familial hypercholesterolemia families with ten informative meiosis cases (Lee 1998). This variant is also reported in ClinVar (Variation ID: 3739). This variant is found in the general population with an overall allele frequency of 0.0096% (3/31402 alleles) in the Genome Aggregation Database. The cysteine at codon 184 is highly conserved, is involved in disulfide bond formation of LDLR, and computational analyses predict that this variant is deleterious (REVEL: 0.854). Based on available information, this variant is considered to be pathogenic -
Homozygous familial hypercholesterolemia Pathogenic:1
The p.Cys184Tyr variant in LDLR (also described as p.Cys163Tyr in the literature) has been reported in >15 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 11 affected relatives from 4 families (Lee 1998, Graham 1999, Fouchier 2001, Wang 2001, Bourbon 2008, Jannes 2015, Martin 2016). It has also been reported by other clinical laboratories in ClinVar (Variation ID 3739). This variant has been identified in 3/15004 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs121908039). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Cys184Tyr variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, very low frequency in the general population and computational evidence. The ACMG/AMP Criteria applied (Richards 2015): PS4, PP1_Strong, PM2, PP3. -
Cardiovascular phenotype Pathogenic:1
The p.C184Y pathogenic mutation (also known as c.551G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 551. The cysteine at codon 184 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been described in numerous familial hypercholesterolemia (FH) cohorts (Hobbs HH et al. Hum. Mutat. 1992;1(6):445-66; Graham CA et al. Atherosclerosis. 1999;147(2):309-16; Hooper AJ et al. Atherosclerosis. 2012;224(2):430-4; Taylor A et al. Clin Genet. 2010; 77(6):572-80; Wang J et al. Arterioscler. Thromb. Vasc. Biol. 2016;36:2439-2445). In one study, this variant was observed to co-segregate with FH in multiple relatives from three families (Lee WK et al. J Med Genet. 1998;35(7):573-8). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 4 (Ambry internal data). Another alteration at the same codon, p.C184R (c.550T>C), has also been described in patients with FH (Pimstone SN et al. Arterioscler Thromb Vasc Biol. 1998;18(2):309-15). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at