rs879254367

Positions:

• chr19-11089397-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 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:7 U:1
• Conservation: PhyloP100: 3.66

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 Likely_pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 250945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11089397-C-T is described in Lovd as [Pathogenic]. Variant chr19-11089397-C-T is described in Lovd as [Likely_pathogenic].
• 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/exons	MANE	Protein	UniProt
LDLR-AS1	NR_163945.1	n.263G>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

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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000106

Gnomad4 OTH exome AF: 0.0000378

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 15, 2023	This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 10484771, 16250003, 16542394, 30293936, 34037665). It has been reported to co-segregate with disease in one family (PMID: 10484771). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Functional studies suggest that this variant has a deleterious effect on the protein (PMID: 10484771). -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, flagged submission	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Mar 03, 2019	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Familial hypercholesterolemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 30, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2021

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

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: rs879254367; hg19: chr19-11200073;