rs879254367

Variant names:

• chr19-11089397-C-T
• rs879254367
• NR_163945.1:n.263G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: LDLR-AS1 NR_163945.1 non_coding_transcript_exon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 3.66
• Publications: 5 publications found

Genes affected

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 (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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307752 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 250945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.-152C>T		upstream_gene_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.-152C>T		upstream_gene_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000860 AC: 4 AN: 465096 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 243796

African (AFR) AF: 0.00 AC: 0 AN: 12816

American (AMR) AF: 0.00 AC: 0 AN: 19860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14020

East Asian (EAS) AF: 0.00 AC: 0 AN: 30542

South Asian (SAS) AF: 0.00 AC: 0 AN: 46626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1968

European-Non Finnish (NFE) AF: 0.0000106 AC: 3 AN: 281748

Other (OTH) AF: 0.0000378 AC: 1 AN: 26458

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000296 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4 Uncertain:1

Mar 03, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Aug 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the 5' untranslated region of the LDLR gene. In vitro functional studies have shown that this variant causes a 30-40% reduction in LDLR promoter activity (PMID: 10484771, 31395865). This variant has been reported in more than 10 unrelated individuals affected with familial hypercholesterolemia (PMID: 10484771, 11005141, 16542394, 30293936, 34037665, 34407635). It has been shown that this variant segregates with disease in three affected individuals from one family (PMID: 10484771). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial hypercholesterolemia Pathogenic:3

Apr 30, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 28, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the 5' untranslated region of the LDLR gene. In vitro functional studies have shown that this variant causes a 30-40% reduction in LDLR promoter activity (PMID: 10484771, 31395865). This variant has been reported in more than 10 unrelated individuals affected with familial hypercholesterolemia (PMID: 10484771, 11005141, 16542394, 30293936, 34037665, 34407635). It has been shown that this variant segregates with disease in three affected individuals from one family (PMID: 10484771). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiovascular phenotype Pathogenic:1

Mar 26, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.96
PhyloP100		3.7
PromoterAI		-0.024	Neutral
Mutation Taster		=268/32	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879254367; hg19: chr19-11200073;