rs879254367
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NR_163945.1(LDLR-AS1):n.263G>A variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0000086 in 465,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000086 ( 0 hom. )
Consequence
LDLR-AS1
NR_163945.1 non_coding_transcript_exon
NR_163945.1 non_coding_transcript_exon
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.66
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-11089397-C-T is Pathogenic according to our data. Variant chr19-11089397-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 250945.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=1, Pathogenic=1}. Variant chr19-11089397-C-T is described in Lovd as [Pathogenic]. Variant chr19-11089397-C-T is described in Lovd as [Likely_pathogenic].
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.1). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR-AS1 | NR_163945.1 | n.263G>A | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000559340.2 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000860 AC: 4AN: 465096Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0AN XY: 243796
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4Uncertain:1
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Uncertain significance, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Mar 03, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 15, 2023 | This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 10484771, 16250003, 16542394, 30293936, 34037665). It has been reported to co-segregate with disease in one family (PMID: 10484771). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Functional studies suggest that this variant has a deleterious effect on the protein (PMID: 10484771). - |
Likely pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 10484771, 11005141, 16542394; Invitae). This variant is also known as c.-59C>T. ClinVar contains an entry for this variant (Variation ID: 250945). Studies have shown that this variant alters LDLR gene expression (PMID: 10484771). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Apr 30, 2019 | The c.-152C>T variant in the LDLR gene sits upstream of the coding region and is predicted to reduce promoter activity of the gene. This variant is not observed in general population databases but has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 11005141, 16542394). Functional studies have shown reduced promoter activity of the LDLR gene when this variant is present (PMID: 10484771). The c.-152C>T variant in the LDLR gene is classified as likely pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 26, 2021 | The c.-152C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 152 bases upstream from the first translated codon. This variant (also described as c.-59C>T) has been reported in individuals with familial hypercholesterolemia (Scholtz CL et al. Hum Mol Genet, 1999 Oct;8:2025-30; Khoo KL et al. Clin Genet, 2000 Aug;58:98-105; Brusgaard K et al. Clin Genet, 2006 Mar;69:277-83). Functional studies showed reduction in promoter activity and transcription (Scholtz CL et al. Hum Mol Genet, 1999 Oct;8:2025-30; Kircher M et al. Nat Commun, 2019 08;10:3583). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at