Variant chr19-11089429-C-T details in Genebe, Genetics Data Aggregator

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]

LDLR links:

LDLR-AS1 (HGNC:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]

LDLR-AS1 links:

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.-120C>T		upstream_gene_variant		ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.-120C>T		upstream_gene_variant		1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000311

AC:

AN:

610234

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

319782

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000175

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000336

Gnomad4 OTH exome

AF:

0.000158

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4Uncertain:6Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4Uncertain:2Benign:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Apr 17, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 20, 2024	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. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing;in vitro	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Mar 27, 2017	A functional analysis was previously published (Francova et al, 2004). Only 3% of activity in comparing with wt promoter. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Familial hypercholesterolemia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 02, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2023	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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2020

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr19-11089429-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over