rs879254366

Positions:

• chr19-11089396-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NR_163945.1(LDLR-AS1):​n.264G>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 0.00000813 in 614,882 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: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: LDLR-AS1 NR_163945.1 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7
• Conservation: PhyloP100: 2.26

Genes affected

LDLR-AS1 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.09).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR-AS1	NR_163945.1	n.264G>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 AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000432 AC: 2 AN: 462740 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 242544

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000329

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000357

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	Disrupt Sterol Regulatory Element sequence. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This variant is located in the conserved sterol-dependent regulatory element 2 (SRE2) in the promoter region of the LDLR gene. This variant is also known as -60C>T based on the position calculated from the transcription start site (PMID: 15303010). An experimental luciferase-based functional assay has suggested that this variant may reduce LDLR promoter activity significantly, but actual data were not shown (PMID: 15303010). Another experimental functional study using high-throughput screening has shown that this variant causes an approximately 40% repression in promoter activity (PMID: 31395865). To our knowledge, it has not been shown whether this variant results in reduced LDLR expression and function in individuals carrying this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15303010, 35052492; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2024	Published functional studies suggest a damaging effect through impaired promoter activity (PMID: 31395865); Reliable data are not available in large population cohorts to assess the frequency of this variant in publicly available databases; however, this variant has not been detected at significant frequency in presumably healthy individuals tested at GeneDx.; Also known as c.-60C>T; This variant is associated with the following publications: (PMID: 17625505, 23315997, 15303010, 21310417, 22698793, 35052492, 38955586, 31395865) -

Familial hypercholesterolemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 12, 2021	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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 15303010). This variant is also known as c.-60C>T. ClinVar contains an entry for this variant (Variation ID: 250944). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 15, 2023	This variant is located in the conserved sterol-dependent regulatory element 2 (SRE2) in the promoter region of the LDLR gene. This variant is also known as -60C>T based on the position calculated from the transcription start site (PMID: 15303010). An experimental luciferase-based functional assay has suggested that this variant may reduce LDLR promoter activity significantly, but actual data were not shown (PMID: 15303010). Another experimental functional study using high-throughput screening has shown that this variant causes an approximately 40% repression in promoter activity (PMID: 31395865). To our knowledge, it has not been shown whether this variant results in reduced LDLR expression and function in individuals carrying this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15303010, 35052492; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.-153C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 153 bases upstream from the first translated codon. This variant (also referred to as -60C>T) has been detected in individuals with hypercholesterolemia; however, reported cases may overlap (Francová H et al. J Inherit Metab Dis. 2004 ;27(4):523-8; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Ambry internal data). Functional studies have suggested that this variant may reduce promoter activity; however, experimental data was not provided by one study (Francová H et al. J Inherit Metab Dis. 2004 ;27(4):523-8; Kircher M et al. Nat Commun, 2019 Aug;10:3583). This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited 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	-0.090
CADD	Benign	20
DANN	Benign	0.96

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

Other links and lift over

dbSNP: rs879254366; hg19: chr19-11200072;