rs879254364
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP5_StrongBP4
The NR_163945.1(LDLR-AS1):n.267G>A variant causes a non coding transcript exon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
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 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-11089393-C-T is Pathogenic according to our data. Variant chr19-11089393-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 250942.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4}. Variant chr19-11089393-C-T is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.11). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR-AS1 | NR_163945.1 | n.267G>A | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000559340.2 | upstream_gene_variant | 5 | ENSP00000453696 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 455202Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0AN XY: 238662
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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455202
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5
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238662
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:2
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Mar 20, 2023 | The NM_000527.4(LDLR):c.-156C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting, PS4_supporting, PP4) 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PS3_supporting - Level 3 assay: PMID 31395865: Heterologous cells, luciferase assays - result - luciferase activity 15-17% of wild-type (repressing variant). ---- functional study is consistent with damaging effect. PS4_supporting - Variant meets PM2 and is identified in 2 index cases with definite FH: 1 index case with CT=439, LDL=377, severe CAD and Achilles tendon xanthomata from Germany (PMID: 14974088), and 1 index case with LDL >13 mmol/L, pCHD and tendon xanthomas from Italy (PMID: 31947532). PP4 - Variant meets PM2 and is identified in 2 index cases with definite FH (see PS4 for details), after alternative causes for high cholesterol were excluded. - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This variant is located in the SREBP binding site in the promoter region of the LDLR gene. An experimental functional study measuring luciferase activity in transfected HepG2 cells has shown that this variant causes a significant decrease in LDLR gene expression (PMID: 31395865). This variant has been reported in four heterozygous individuals affected with familial hypercholesterolemia (PMID: 14974088, 21382890, 28104544, 33740630). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 31947532, 32977124). It has been shown that this variant segregates with disease in two affected individuals in one family (PMID: 14974088). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2024 | The c.-156C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 156 nucleotides upstream from the first translated codon, and is located in the sterol regulatory element (SRE-1). This variant was reported to occur in the homozygous state in an individual with features consistent with homozygous familial hypercholesterolemia (FH) including severe, early onset coronary artery disease, LDL-C of 377mg/dL, Achilles tendon xanthoma, periorbital xanthelasma, and sudden death who also had a family history of heart attack, sudden death, and hypercholesterolemia; a reportedly less severely affected sibling was heterozygous for the variant (Dedoussis GV et al. Hum. Mutat., 2004 Mar;23:285-6). This has also been detected in the heterozygous state in individuals with features consistent with heterozygous FH or individuals from FH cohorts; however, in some cases clinical details were limited (van der Graaf A et al. Circulation. 2011 Mar;123(11):1167-73; Durst R et al. Atherosclerosis, 2017 02;257:55-63; Leren TP et al. Atherosclerosis. 2021 Apr;322:61-66). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | LDLR: PM1, PM2 - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 21, 2022 | 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 hypercholesterolemia (PMID: 14974088, 21382890, 28104544, 32977124, 33740630). ClinVar contains an entry for this variant (Variation ID: 250942). Studies have shown that this variant alters LDLR gene expression (PMID: 31395865). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Calibrated prediction
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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