rs879254476
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.324_325delinsTC(p.Cys109Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T108T) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.99
Genes affected
LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
?
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000527.5
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-11105230-GT-TC is Pathogenic according to our data. Variant chr19-11105230-GT-TC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.324_325delinsTC | p.Cys109Arg | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.324_325delinsTC | p.Cys109Arg | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | May 11, 2018 | The deletion of the two nucleotides GT and the insertion of the two nucleotides TC at position 324 leads to the amino acid exchange cysteine to arginine (p.Cys109Arg). This mutation has already been described in patients with hypercholesterolemia and is therefore classified as pathogenic. We diagnosed this variant in a patient with FH at the age of 17. PMID: 11313767, 14974088, 16314194 - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 28, 2023 | This missense variant deletes 2 nucleotides and inserts 2 nucleotides, resulting in the replacement of cysteine with arginine at codon 109 in the LDLR type A repeat 3 of the LDLR protein. This variant is also known as p.Cys88Arg in the mature protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11313767, 20145306, 34037665, 35741760; ClinVar SCV000503139.1 and SCV000987024.1). A different missense variant occurring at the same codon and causing the same amino acid change, c.325T>C (p.Cys109Arg), is known to be disease-causing (ClinVar variation ID: 251156). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
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 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 16, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 17, 2023 | This missense variant deletes 2 nucleotides and inserts 2 nucleotides, resulting in the replacement of cysteine with arginine at codon 109 in the LDLR type A repeat 3 of the LDLR protein. This variant is also known as p.Cys88Arg in the mature protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11313767, 20145306, 34037665, 35741760; ClinVar SCV000503139.1 and SCV000987024.1). A different missense variant occurring at the same codon and causing the same amino acid change, c.325T>C (p.Cys109Arg), is known to be disease-causing (ClinVar variation ID: 251156). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 109 of the LDLR protein (p.Cys109Arg). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11313767, 14974088, 19843101, 20145306, 22698793). ClinVar contains an entry for this variant (Variation ID: 251154). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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). This variant disrupts the p.Cys109 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 1131376, 9544745, 12009418), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 2988123, 12459547, 34037665, 11313767, 20145306, 35741760) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 08, 2023 | The c.324_325delGTinsTC pathogenic mutation, located in coding exon 4 of the LDLR gene, results from an in-frame deletion of GT and insertion of TC at nucleotide positions 324 to 325. This results in the substitution of the cysteine residue for an arginine residue at codon 109, 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). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 domain (Ambry internal data). This variant, which is also known as p.C88R, has been reported in individuals with familial hypercholesterolemia (FH) (Heath KE et al. Eur J Hum Genet, 2001 Apr;9:244-52; Chmara M et al. J Appl Genet, 2010;51:95-106; Sturm AC et al. JAMA Cardiol, 2021 Aug;6:902-909; Rutkowska L et al. Genes (Basel), 2022 Jun;13:[ePub ahead of print]). Another nucleotide change at the same codon that results in the same amino acid change, c.325T>C (p.C109R), which is also known as FH Munster-1, has been reported in individuals with familial hypercholesterolimia (FH) from a number of ethnic groups (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Fouchier SW et al. Hum Mutat. 2005;26:550-6; Robles-Osorio L et al. Arch Med Res. 2006;37:102-8; Tichý L et al. Atherosclerosis. 2012;223:401-8). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at