chr19-11089429-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NR_163945.1(LDLR-AS1):n.231G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000275 in 762,544 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 Uncertain significance (★★★).
Frequency
Consequence
NR_163945.1 non_coding_transcript_exon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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LDLR | NM_000527.5 | c.-120C>T | upstream_gene_variant | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000311 AC: 19AN: 610234Hom.: 0 Cov.: 8 AF XY: 0.0000281 AC XY: 9AN XY: 319782
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74478
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4Uncertain:2Benign:1
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A functional analysis was previously published (Francova et al, 2004). Only 3% of activity in comparing with wt promoter. -
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The NM_000527.4(LDLR):c.-120C>T variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP4, PS3_Supporting, PS4_Supporting and BP2 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 = 0.00001470 (0.001470%) in European non-Finnish (gnomAD v3.2.1). It is below 0.02%, so met. PP1 - Variant segregates with the FH phenotype in: - 2 relatives from 1 family from Francová et al. 2004 (PMID: 15303010): 2 relatives with the phenotype (LDL cholesterol concentration between 93 and 99.5 percentile for age and sex) have the variant; - 1 relative from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 1 relative without the phenotype and without the variant. 3 segregations, so PP1 is met. PS3_supporting - Level 3 FS: Francová et al. 2004 (PMID: 15303010) : Heterologous cells (HepG2), luciferase assays - results: 3% reporter gene transcription (Reported as c.-27C>T in the paper). --- it is below 50%, so PS3_Supporting is met. PS4_supporting - variant meets PM2 and was identified in: - 1 index 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), France; - 1 index case with Simon Broome possible from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; - 1 index case with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia. 3 cases, so PS4_Supporting is met PP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical FH criteria from different labs (please see PS4 for details), so PP4 is met. BP2 - Variant identified in 1 index case and 1 relative, both carriers of NM_000527.4(LDLR):c.2416dupG (p.Val806Glyfs*11) in trans with LDLc values of 4.3 mmol/l (16y) and 5.9 mmol/l (11y), respectively. 2nd variant is classified as Pathogenic by these guidelines and phenotype is clearly of heterozygous FH, so BP2 is met. -
This variant (also known as -27C>T , counting from the transcription start site) changes a conserved nucleotide in the promoter region of the LDLR gene. An experimental functional study has shown that this variant abolishes the promoter activity in a luciferase-based assay performed in HepG2 cells (PMID: 15303010). However, this variant has shown no significant impact on the promoter activity in a similar luciferase-based assay performed in Huh7 cells (PMID: 25248394), as well as in a similar assay performed in HEK293 cells (PMID: 31395865). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 30293936) and in 3 related individuals affected with familial hypercholesterolemia (PMID: 15303010). This variant has also been reported in a 70-year old individual with very low Dutch Lipid Clinical Network-score (PMID: 29974534). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting functional study results and insufficient clinical evidence, the role of this variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Familial hypercholesterolemia Uncertain:2
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 present in population databases (no rsID available, gnomAD 0.03%). This variant has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 15303010, 21538688, 30293936, 34456049, 35047021). ClinVar contains an entry for this variant (Variation ID: 226299). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LDLR function (PMID: 15303010). 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. -
This variant (also known as -27C>T , counting from the transcription start site) changes a conserved nucleotide in the promoter region of the LDLR gene. An experimental functional study has shown that this variant abolishes the promoter activity in a luciferase-based assay performed in HepG2 cells (PMID: 15303010). However, this variant has shown no significant impact on the promoter activity in a similar luciferase-based assay performed in Huh7 cells (PMID: 25248394), as well as in a similar assay performed in HEK293 cells (PMID: 31395865). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 30293936) and in 3 related individuals affected with familial hypercholesterolemia (PMID: 15303010). This variant has also been reported in a 70-year old individual with very low Dutch Lipid Clinical Network-score (PMID: 29974534). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting functional study results and insufficient clinical evidence, the role of this variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); Functional studies are conflicting as to whether this variant significantly alters promoter activity (Francova et al., 2004; Khamis et al., 2015; Kircher et al., 2019); Also known as -27C>T; This variant is associated with the following publications: (PMID: 31395865, 21310417, 22698793, 29974534, 15303010, 21538688, 34456049, 30293936, 25248394, 35047021) -
Cardiovascular phenotype Uncertain:1
The c.-120C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 120 bases upstream from the first translated codon. This alteration has been reported to segregate with disease in one small family with familial hypercholesterolemia (FH) (Francová H et al. J. Inherit. Metab. Dis., 2004;27:523-8; described as c.-27C>T). This variant has also been reported in an FH genetic testing cohort, but clinical details were limited (Martín-Campos JM et al. J Clin Lipidol Oct;12:1452-1462). Functional studies performed in vitro suggest that this variant may reduce LDLR transcription levels, but while one study suggested that this alteration reduced transcription to background levels, two other studies suggest that the variant reduces transcription by only 10-17%, and the clinical relevance of that degree of reduction is unclear (Francová H et al. J. Inherit. Metab. Dis., 2004;27:523-8; Khamis A et al. Eur. J. Hum. Genet., 2015 Jun;23:790-5; Kircher M et al. Nat Commun, 2019 08;10:3583). This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at